Sustained release bactericidal cannula

ABSTRACT

A sustained release bactericidal cannula or catheter for residence within a portion of a human body through which aqueous biological fluids can pass. The bactericidal cannula for catheter including a tube having an inner surface, defining and interior lumen, and an outer surface. The tube has a polymeric matrix and antibacterial agent residing within at least a portion of the polymeric matrix. The polymeric matrix includes cured silicon rubber and the antibacterial agent is a finely divided nitrofuran compound which is soluble in water and effective to prevent proliferation of certain bacteria in an otherwise growth supporting aqueous environment when dissolved in the aqueous environment to the limit of its solubility therein at 37° C. The solubility of the nitrofuran compound is preferably about 0.2% by weight or less at a pH of about 6 and a temperature of about 25° C. The antibacterial agent can diffuse out of the polymeric matrix and into an aqueous biological environment when the polymeric matrix comes into contact with such an aqueous biological environment. Preferably, at least a finite portion of the polymeric matrix proximate the outer surface includes an amount of from about 10 to about 60% by weight of the nitrofuran compound and the amount of the nitrofuran compound and the solubility thereof cooperate to provide a potential for a sustained release diffusion thereof for a period of not less than about three weeks during normal use of the cannula within the human body. Methods of making a sustained release bactericidal cannula and of catheterizing a patient are also disclosed.

CROSS-REFERENCE TO OTHER APPLICATIONS

The present application is a continuation-in-part application ofco-pending U.S. patent application Ser. No. 07/489,462, filed Mar. 6,1990, now abandoned, which is a continuation-in-part application ofco-pending U.S. patent application Ser. No. 07/487,422, filed Mar. 1,1990, now U.S. Pat. No. 5,098,379, which is a continuation-in-partapplication of co-pending U.S. patent application Ser. No. 07/462,832,filed Jan. 10, 1990, now U.S. Pat. No. 5,137,671, the disclosures ofwhich are each incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to sustained release bactericidal cannulasor catheters which are either implantable or insertable into a humanbody. These devices have an antibacterial agent incorporated within thedevice which diffuse out in situ to prevent the proliferation orcolonization of bacteria in regions adjacent to the exterior of thecannula or catheter. The present invention also relates to methods formaking the same, products made by these methods, and methods of usingthe sustained release bactericidal cannulas or catheters, to preventproliferation, colonization or continued viability of a bacterialpopulation in regions adjacent to the exterior of the respective cannulaor catheter.

BACKGROUND OF THE INVENTION

Most catheters are a cannula or tube like device which is inserted intoa portion of a person's body in order to transport fluids or gases in orout of that particular portion of the body. In passing through anyparticular portion of the body in order to reach its destination, thecatheter will come into contact with various tissues in the body. Forexample, a catheter used to drain one's bladder (such as a "Foley"catheter) must pass through the urethral tract in order to reach thebladder. A nasogastric catheter must pass through the nasal passagewayand the esophagus in order to reach the stomach. Some catheters, such asthese, are inserted through existing passageways in order to reach theirdestinations, while others are inserted through surgically createdpassageways.

In virtually every catheterization, there is a significant potential formicrobial growth along the exterior surface of the catheter which canlead to serious infections such as urinary tract infections, bladderinfections and the like. Such an infection can be encouraged whenadjacent tissues are inflamed due to irritation from rubbing a chafingagainst this catheter. This is because inflamed or irritated tissues maybe less apt to respond effectively to suppress local bacterialinfection. In such a situation the infection can spread and intensify,placing the patient at further risk. Such infections can lead to sepsisof the bladder particularly in elderly patients who are incontinent andhave a chronic need for catheterization with an indwellingself-retaining catheter such as a "Foley" catheter. Long-term use ofindwelling urinary catheters in nursing home patients is well known as apotential cause of significant morbidity due to such infections.

This problem is widely recognized and many solutions for this problemhave been suggested in the past. None of these solutions, however, havebeen completely free of secondary complications and/or completelysuccessful in eliminating the problem. For instance, systemic use ofantibacterial drugs or agents have been tried. However, these drugsgenerally have undesirable secondary effects upon the patient when usedsystemically, especially when there is a chronic need forcatheterization and the drug must employed for a long period of time.Local use of such drugs or agents can be effective for a short period oftime, but has not been found to be effective for long-term use for anumber of reasons. First, the drug or agent is easily washed out ifthere is a leakage of urine through the urinary track outside of thecatheter. Second, the drug or agent may be delivered only to certainareas of the urinary tract and, third, the drug or agent may be absorbedby the body tissues adjacent to the catheter and transported elsewherewithin the body.

Other methods of preventing periurethral contamination have beensuggested. These include careful cleansing of the periurethral area on aroutine basis, impregnating a sponge or the like with an antisepticsolution and retaining it in a position proximate the urethral, applyantimicrobial ointments to an external portion of the urinary tract,intraurethral irrigation of the urinary track through a separatechannel, lubrication of the catheter with an antibiotic-containingmaterial and the use of catheters impregnated with antimicrobial agents.Each of these methods has been explored and none have been found to beentirely satisfactory. In vitro tests of impregnated catheters indicatethat the antibacterial agents within the catheters have a tendency toleach or diffuse out of the catheters in a short period of time. Often,the antibacterial activity was either gone or markedly diminished within24 to 48 hours of insertion within the urethral tract. Therefore, itwould be appreciated that a sustained release bactericidal cannula orcatheter is needed in order to address the needs of patients requiringlong-term catheterization or the like.

Accordingly, it will be appreciated that there is a need for a medicaldevice, cannula or catheter which will address these and other problemsassociated with the prior art devices. The present invention providesadvantages over the prior art cannulas and catheters, over the prior artmethods for manufacturing the same, and also offers other advantagesover the prior art and solves other problems associated therewith.

SUMMARY OF THE INVENTION

Accordingly, a sustained release bactericidal cannula for residencewithin a portion of a human body through which aqueous biological fluidscan pass is provided. The sustained release bactericidal cannulacomprises a tube having an inner surface, defining an internal lumen,and an outer surface. The tube has a polymeric matrix and anantibacterial agent residing within at least a portion of the polymericmatrix, wherein the polymeric matrix preferably includes cured siliconrubber, said bacterial agent is preferably a finely divided nitrofuranwhich is soluble in water and effective to prevent proliferation ofcertain bacteria in an otherwise growth supporting aqueous environmentwhen dissolved in the aqueous environment to the limit of its solubilitytherein at 37° C. Preferably the nitrofuran compound has a solubility ofabout 0.2% by weight or less in water at a pH of about 6 and atemperature of about 25° C. The antibacterial agent can diffuse out ofthe polymeric matrix and into an aqueous biological environment when thepolymeric matrix comes into contact with such an aqueous biologicalenvironment. Preferably, at least a finite portion of the polymericmatrix proximate the outer surface preferably includes an amount of fromabout 10 to about 60% by weight of the nitrofuran compound, and thenitrofuran compound in the finite portion of the polymeric matrix andthe solubility of the nitrofuran compound cooperate to provide apotential for a sustained release diffusion of the antibacterial agentinto the aqueous biological fluids within the human body, during normaltherapeutic use of the cannula therein, so long as the aqueousbiological fluids are not saturated with the antibacterial agent, suchthat the antibacterial agent within the finite portion of the polymericmatrix can continue to diffuse into the aqueous biological fluids withinthe human body in an amount effective to prevent proliferation ofcertain bacteria immediately adjacent to the cannula in aqueousbiological environments for a period of not less than about three weeks.In preferred embodiments the cannula is a urinary catheter for residencewithin a urinary track, preferably a "Foley" catheter having anexpandable balloon cavity, a second lumen in communication with theexpandable balloon cavity and a coating on at least a portion of theexterior surface of the catheter proximate the balloon cavity which ispreferably a cured silicon rubber polymeric matrix incorporating anantibacterial agent capable of diffusing out of the polymeric matrix inaqueous environments. Preferably, the rate of diffusion of theantibacterial agent from the polymeric matrix can increase when theexpandable balloon portion expands.

It is an object of the present invention to provide a sustained releasebactericidal cannula or catheter which can be used on a long-term basisto reduce or eliminate the incidence of urinary tract infections inpatients having a chronic need for catheterization. The presentinvention provides a catheter having a large percentage of activeantibacterial agent incorporated into a cured silicon rubber outercoating. Preferably, the antibacterial agent is a finely dividednitrofuran compound having a solubility of about 0.2% by weight or less.In preferred embodiments the mean particle size of the nitrofurancompound particles is about 200 microns or less in order to allow for avery smooth outer surface on the cannula or catheter. This is importantto reduce the incidence of irritation of the tissues within the urinarytract. It will be appreciated that it is especially difficult toincorporate a large percentage of a solid antibacterial agent within apolymeric matrix and still provide a smooth outer surface, as well assufficient flexibility and durability so as to suitable for the intendeduse. In preferred embodiments of the present invention the mean particlesize of the nitrofuran compound particles is about 100 microns or lessenabling the incorporation of this antibacterial agent at an even higherpercentage in the polymeric matrix, while still retaining the desiredsmoothness, flexibility and durability of the outer coating.

These and various other advantages and features of novelty whichcharacterize the present invention are pointed out with particularity inthe claims annexed hereto and forming a part hereof. However, for abetter understanding of the present invention, its advantages and otherobjects obtained by its use, reference should be made to the drawings,which form a further part hereof, and to the accompanying descriptivematter, in which there is illustrated and described preferredembodiments of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, in which like and primed, reference numerals indicatecorresponding parts throughout the several views,

FIG. 1 is a transverse schematic view of an extruded double lumen tubein partial cross-section;

FIG. 2 is a cross-sectional view of the extruded double lumen tube asseen from the line 2--2 of FIG. 1;

FIG. 3 is a transverse schematic view of the tube shown in partialcross-section in FIG. 1 after an opening is punched in the outersurface;

FIG. 4 is a cross-sectional view of the tube as shown from the line 4--4of FIG. 3;

FIG. 5 is a transverse schematic view of the double lumen tube shown inpartial cross-section in FIG. 3 after a portion of the first lumen hasbeen filled with a polymeric bonding composition;

FIG. 6 is a cross-sectional view of the tube as seen from the line 6--6of FIG. 5;

FIG. 7 is a transverse schematic view of the double lumen tube shown inpartial cross-section in FIG. 5 after a tip is affixed to a distal endof the tube;

FIG. 8 is a schematic view of a portion of a rack used to retain aplurality of tubes during a series of dipping steps;

FIG. 9 is a transverse schematic view of an intermediate tube in partialcross-section similar to the tube shown in FIG. 7 at an intermediatestage of manufacture prior to the first of a series of dipping steps;

FIG. 10 is a transverse schematic view of an intermediate tube inpartial cross-section similar to that shown in FIG. 9, but following afirst dipping step wherein the outer surface is coated with a bondpreventing agent up to the point designated by line A;

FIG. 11 is a cross-sectional view of the intermediate tube of FIG. 10 asshown from the line 11--11;

FIG. 12 is a view of an intermediate tube in partial cross-sectionsimilar to that shown in FIG. 10, but after a subsequent dipping step orsteps in which the coating of bond preventing agent on a portion of theouter surface of the intermediate tube has been removed;

FIG. 13 is a transverse schematic view of a portion of a ballooncatheter formed from the intermediate tube shown in FIG. 12 in partialcross-section, following a plurality of dipping steps to create anovercoat layer;

FIG. 14 is a cross-sectional view of the balloon catheter shown in FIG.13 from the line 14--14;

FIG. 15 is transverse schematic view of a portion of a coated ballooncatheter formed from the balloon catheter shown in FIG. 13 in partialcross-section, following a further coating step to create an outerbactericide release layer;

FIG. 16 is a cross-sectional view of the balloon catheter shown in FIG.15 from the line 16--16;

FIG. 17 is a transverse schematic view of a Foley catheter made inaccordance with the present invention following testing and cleaning andshowing sectional views of portions thereof;

FIG. 18 is a schematic view of a portion of the Foley catheter shown inFIG. 15, but with the balloon portion of the catheter shown whenexpanded;

FIG. 19 is a schematic illustration of apparatus used to automate theproduction of balloon catheters in accordance with the presentinvention;

FIG. 20a, 20b and 20c are flow charts representing certain steps inaccordance with the present invention;

FIG. 21 is a transverse schematic view of an alternate extruded doublelumen tube in partial cross-section;

FIG. 22 is a cross-sectional view of the alternate extruded double lumentube as seen from the line 22--22 of FIG. 21;

FIG. 23 is a transverse schematic view of the alternate tube shown inFIG. 21 after an opening is punched in the outer surface;

FIG. 24 is a cross-sectional view of the alternate tube as shown fromthe line 24--24 of FIG. 23;

FIG. 25 is a transverse schematic view of the alternate double lumentube shown in FIG. 23 after a portion of the first lumen has been filledwith a polymeric bonding composition;

FIG. 26 is a cross-sectional view of the alternate tube as seen from theline 26--26 of FIG. 25;

FIG. 27 is a transverse schematic view of the alternate double lumentube shown in FIG. 25 after a tip is affixed to a distal end of thetube;

FIG. 28 is a schematic view of a portion of a rack or pallet used toretain a plurality of tubes during a series of dipping steps;

FIG. 29 is a transverse schematic view of an alternate intermediate tubein partial cross-section similar to the alternate tube shown in FIG. 27at an intermediate stage of manufacture following the first of a seriesof dipping steps which creates a coating of bond preventing lubricatingagent on the outer surface;

FIG. 30 is a transverse schematic view of the alternate intermediatetube shown in FIG. 29, but following a second dipping step wherein thecoating of bond preventing lubricating agent on the outer surface hasbeen partially removed;

FIG. 31 is a cross-sectional view of the intermediate tube of FIG. 30 asshown from the line 31--31;

FIG. 32 is a transverse schematic view of the alternate intermediatetube shown in FIG. 30, but after a subsequent dipping step creating asecond coating of bond preventing lubricating agent on a portion of theouter surface removed form the portion which remains coated by the firstcoating;

FIG. 33 is a transverse schematic view of the alternate intermediatetube shown in FIG. 32, but after yet another dipping step or stepdesigned to remove the second coating from a further portion of theouter surface;

FIG. 34 is a cross-sectional view of the balloon catheter shown in FIG.33 from the line 34--34;

FIG. 35 is a transverse schematic view of the intermediate tube shown inFIG. 33, following a further dipping step or steps to create an overcoatlayer;

FIG. 36 is a transverse schematic view in partial cross-section of aportion of an alternate balloon catheter formed from the alternateintermediate tube shown in FIG. 35, following a further dipping step orsteps to create an outer bactericide release layer;

FIG. 37 is a perspective view of a portion of the balloon catheter shownin FIG. 35 in partial cross-section, but wherein the balloon catheterhas been severed through the sleeve cavity and the remaining portion ofthe sleeve has been twisted to demonstrate its independence of the outersurface of the extruded double lumen tube used to make the ballooncatheter;

FIG. 38 is a transverse schematic view of the balloon catheter shown inFIG. 35, but in partial cross-section, but including an end piece andshowing a sectional view of a portion of the catheter wherein theballoon portion of the catheter is expanded;

FIG. 39 is a transverse schematic view in partial cross-section of yetanother embodiment of the present invention similar to that shown inFIG. 38;

FIG. 40 is a transverse schematic sectional view showing a portion ofthe catheter shown in FIG. 39 when inserted in a urethral tract;

FIG. 41 is a schematic illustration of apparatus used to automate theproduction of catheters in accordance with the present invention;

FIG. 42a, 42b and 42c are flow charts illustrating certain steps inmethods in accordance with the present invention;

FIG. 43 is a transverse schematic view of another alternate extrudedtube in partial cross-section;

FIG. 44 is a transverse schematic view of an alternate intermediate tubeformed from the alternate extruded tube shown in FIG. 43;

FIG. 45 is a schematic view in partial cross-section of a portion of analternate rack or pallet used to retain a plurality of alternateintermediate tubes during a series of steps designed to provide thetubes with overcoat layers of a polymeric bonding composition, wherein asingle alternate intermediate tube like that shown in FIG. 44 is shownsecured to a single support rod following a first dipping step wherein aportion of the outer surface of the alternate intermediate tube iscoated with a bond preventing lubricating material;

FIG. 46 is a transverse schematic view of the alternate intermediatetube shown in FIGS. 43 and 44, but following a second dipping stepwherein the coating of bond preventing lubricating material on the outersurface of the alternate intermediate tube has been partially removed;

FIG. 47 is a transverse sectional schematic view of the alternateintermediate tube shown in FIG. 46 following a subsequent dipping stepor steps in which an overcoat layer is formed over the outer surfacethereof;

FIG. 48 is a transverse sectional schematic view of the alternateintermediate tube shown in FIG. 47 following a subsequent dipping stepor steps in which an outer bactericide release layer is formed over aportion of the overcoat layer; and

FIG. 49 is a transverse schematic view in partial cross-section of anelongated catheter in accordance with the present invention which ismade from the alternate intermediate tube shown in FIG. 48.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Referring now generally to the drawings, and specifically to thecannulas and catheters 4, 5 shown in FIGS. 15-18; 4', 5' shown in FIGS.36-38; 4", shown in FIGS. 39 and 40; and 4'" shown in FIGS. 48 and 49,the present invention provides cannulas and/or catheters 4, 5 having anouter bactericide release layer 61 which is capable of a sustainedrelease or diffusion of an antibacterial agent into aqueous environmentsproximate the outer bactericide release layer 61. The outer bactericiderelease layer 61 is preferably a cured silicon rubber polymeric matrix.Impregnated within the cured silicon rubber polymeric matrix is abacterial agent. This bacterial agent is nitrofuran compound having theformula: ##STR1## where R is a carbon-containing organic moiety, such asthat disclosed, for example, in K. Miura et al., entitled "TheNitrofurans," in Progress in Medicinal Chemistry (Vol. 5), pp. 320-381,(G. P. Ellis & G. B. West (eds.), Plenum Press, New York, N.Y. (1967),the disclosure of which is incorporated by reference herein. Thepreferred nitrofurans are nitrofurans which are soluble in water andhave antibacterial activity in aqueous environments.

Preferred nitrofuran compounds include nitrofurantoin, nitrofurazone,nidroxyzone, nifuradene, furazolidone, furaltidone, nifuroxime,nihydrazone, nitrovin, nifurpirinol, nifurprazine, nifuraldezone,nifuratel, nifuroxazide, urfadyn, nifurtimox, triafur, nifurtoinol,nifurzide, nifurfoline, nifuroquine, and derivatives of the same, andother like nitrofurans which are both soluble in water and possessantibacterial activity. References to each of the above cited nitrofurancompounds may be found in the Merck Index, specifically the ninthedition (1976) and the eleventh edition (1989) thereof, published byMerck & Co., Inc., Rahway, N.J., the disclosures of which are eachincorporated herein by reference. It will be appreciated that the mostpreferred nitrofuran compounds are nitrofuran compounds which aremedically acceptable for topical use, preferably topical use for mucosalsurfaces.

Preferably, the nitrofuran compounds have a solubility of about 0.2% byweight or less in water at a pH of about 6 and temperature of about 25°C. More preferably, the nitrofuran compounds have a solubility in waterof about 0.2 to about 0.001% by weight in water at a pH of about 6 and atemperature of about 25° C. Even more preferably, the solubility of thenitrofuran compound under these conditions is about 0.1% by weight orless. It will be appreciated that it is important to have anantibacterial agent which is effective to prevent the proliferation andcolonization of bacteria within aqueous systems, and that it is alsoimportant to have an antibacterial agent which is not so soluble inaqueous systems that it will immediately diffuse out of the polymericmatrix within which it is incorporated. These characteristics areimportant in order to provide a sustained release of the antibacterialagent into these aqueous systems so as to provide for long-termantibacterial activity. It will also be appreciated that the rapidrelease or diffusion of the antibacterial agent into an aqueousenvironment in contact with the outer bactericide release layer 61 willalso result in irregularities in the surface of the catheter or cannula4, 5 which may irritate adjacent tissues within the patient's urinarytract.

It will be further appreciated that it is important that the outersurface of the outer bactericide release layer 61 is smooth so as tominimize the incidence of irritation to the tissues of the urinarytract. In order to provide a smoother outer surface, it is important tominimize the particle size of the finely divided nitrofuran compoundparticles incorporated into the outer bactericide release layer 61. Themean particle diameter of the nitrofuran compound particles ispreferably about 200 microns or less, more preferably bout 150 micronsor less, and even more preferably about 100 microns or less. The size ofthe mean particle diameter is preferably controlled by filtering thelarger particles out of the mixture used to coat the intermediate tubesused to make the finished catheters or cannulas 4, 5.

In preferred embodiments of the present invention, the outer bactericiderelease layer 61 includes silicone fluid which is incorporated thereinto provide for more rapid diffusion of the antibacterial agent uponexposure to aqueous medium. It is believed, but not relied upon, thatthe silicone fluid allows the cured silicone polymeric matrix to providefor greater diffusion of aqueous media into and out of the polymericmatrix. In addition, the silicone fluid is desirable because it providesa softer, more pliable polymeric matrix which is also easier toelongate. It is further believed that the incorporation of the siliconefluid along with the minimization of the mean particle diameter of thenitrofuran compound particles cooperate to maximize the smoothness ofthe outer surface of the outer bactericide release layer 16, and tomaximize the structural integrity, softness and stretchability of therelease layer 61. The structural integrity is also important so that theamount of the antibacterial agent incorporated into the release layer 61can be maximized. It will be appreciated that the greater the structuralintegrity of the polymeric matrix, the less the matrix will break downand disintegrate. If the release layer attached to the catheter orannula 4, 5 disintegrates or flakes off for lack of better bonding, theproduct will be unacceptable in the marketplace. Although it is believedthat the most important factor in this regard is the small particlesize, it is also important to incorporate some silicone fluid to softenthe polymeric matrix and allow it to be more stretchable, therebyminimizing the rigidity of the polymeric matrix. Although it is possibleto use nitrofuran compound particles of virtually any size, it will beappreciated that a mean particle diameter of less than about 500 micronswill be preferred and that even smaller mean particle diameters such asabout 400 microns or less, preferably about 300 microns or less, morepreferably about 200 microns or less, will be more preferred in order tobe able to incorporate more of the drug into the polymeric matrix andstill have a soft and pliable polymeric matrix and a smooth outersurface so as to provide commercially acceptable products. In preferredembodiments of the present invention, the outer bactericide releaselayer 61 preferably includes about 2-80% by weight, more preferablyabout 5-70% by weight, even preferably about 10-60% by weight, and mostpreferably about 15-55% by weight of the nitrofuran compound in thepresent invention, and outer bactericide release layer will include ananti-inflammatory agent in amounts similar to the amounts recited hereinfor the nitrofuran compound. The preferred anti-inflammatory agents arewater soluble, anti-inflammatory agents such as hydrocortisone,hydrocortisone acetate, hydrocortisone phosphate, hydrocortisonehemisuccinate sodium salt, hydrocortisone tebutate, and the like. Inthis regard, it will be appreciated that any therapeutically acceptable,water soluble anti-inflammatory agent may be used in the presentinvention in order to reduce inflammation of the tissues adjacent to thepresent catheter or cannula 4, 5 when inserted in a human body. In analternate embodiment of the present invention, the hydrocortisonecompound has a solubility in water of less than about 0.1% by weight.

In order to provide long-term sustained release antibacterial activity,the present catheter or cannula 4, 5 preferably provides an outerbactericide release layer 61 having a smoother outer surface such thatit minimizes irritation to adjacent tissues. This release layer 61preferably includes about 10-60% by weight of a preferred nitrofurancompound or a combination thereof having a mean particle diameter of 200microns or less. Preferably, the catheter or cannula 4, 5 of the presentinvention provides a potential for sustained release of theantibacterial agent incorporated in the outer bactericide release layer61 for a period of at least about two weeks, preferably at least aboutthree weeks, more preferably at least about four weeks, and even morepreferably about five weeks. In further embodiments, the antibacterialagent is released for periods of at least about six weeks, seven weeks,eight weeks, or more, depending upon the amount of the solid nitrofurancompound which is incorporated into the release layer 61 and thesolubility thereof in water. It will be appreciated, however, thatalthough it is desirable to incorporate a large amount of the nitrofurancompound into the release layer 61, it is also important to retain theelongation characteristics and smoothness which is generally availableto cellastic membranes used on similar catheters or cannulas. It will beappreciated that the rate of release of the nitrofuran compound into thesurrounding aqueous environment is dependent on the rate of fluidexchange. It has been observed that 3 milliliters of fluid exchangegenerally occurs within an average female urinary tract every 24 hours.Because the antibacterial agent concentration in the fluid adjacent tothe release layer 61 will generally release a point of equilibrium withthe antibacterial agent within the release layer 61, the diffusion rateof the antibacterial agent out of the release layer 61 will be slowed asthe concentration reaches maximum solubility for the particularnitrofuran compound incorporated into the release layer 61. Asadditional fluid passes into the urinary tract and dilutes the fluidalready present or washes the fluid out, the diffusion rate willincrease. In this way, the present invention is designed to attempt tomaintain a concentration of the antibacterial agent in the aqueousfluids within the urethra at a level generally commensurate with themaximum solubility of the antibacterial agent. It will be appreciated,however, that this will not always be the case. Therefore, it is alsoimportant to provide a burst of antibacterial agent in the urethra uponinsertion of the catheter or cannula 4, 5 so as to immediately eliminatethe presence of viable bacterial therein. This is accomplished when aFoley catheter 4, 5 such as that shown in FIGS. 15-18 is inserted intothe urinary tract and the expandable balloon portion 58 is expanded,thereby stretching the release layer 61 proximate the expandable balloonportion 58. This increases the diffusion rate of the antibacterial agentfrom the release layer 61 proximate the expandable balloon portion 58and allows for a sudden increase in the concentration of theantibacterial agent in the fluids adjacent to the expandable balloonportion 58.

In the preferred embodiment, nitrofurazone is the nitrofuran compound ofchoice. When using nitrofurazone, it is desirable to maintain anitrofurazone concentration in aqueous fluids adjacent to the catheterat about 0.02% by weight in order to minimize and preferably eliminatebacterial proliferation within the urinary tract. It will be appreciatedthat nitrofurazone is desirable, not only because of its limitedsolubility in water, but also because of its broad antibacterialactivity in respect to both Gram positive and Gram negative bacteriawhich commonly infect the bladder and the urinary tract. It is alsodesirable because of its bright yellow color, which provides anattractive product for commercial presentation. In addition,nitrofurazone appears to stand up rather well to high temperatures usedto cure the silicone rubber within the release layer 61 duringprocessing. Although silicone rubber matrices created from siliconerubber vulcanizing systems which do not require heat, such as RTVsystems and the like, may be cured at ambient temperatures, the heatcured silicone rubber matrices are preferred.

In preferred embodiments, a silicone rubber/nitrofurazone dispersion ormixture is prepared as follows: 100 grams of nitrofurazone powder iswetted with approximately 10 fluid ounces of 1,1,1-trichloroethane(Hydrite Chemical Co., LaCrosse, Wis.). This mixture is agitatedvigorously. In a separate container, 100 grams of uncured siliconerubber (2 parts platinum cure system, 1/2 part A and 1/2 part B (DowCorning, Midland, Mich.)) is dispersed with about 20 grams of siliconefluid (360 fluid, 20 centistoke (Dow Corning, Midland, Mich.)) in aratio of 5 parts to 1 in approximately 10 fluid ounces of1,1,1-trichloroethane (Hydrite Chemical Co., LaCrosse, Wis.). Another 30fluid ounces of 1,1,1 trichloroethane is added to thenitrofurazone/trichloroethane mixture, and agitated continuously. Thenitrofurazone/trichloroethane mixture is passed through a filter toremove the larger nitrofurazone particles. Preferably, two 6-inchcone-shaped filters from TUFCO (medium mesh) are used back-to-back (oneinside the other) to filter the nitrofurazone/trichloroethane mixture.The filtering step is repeated three or four times to remove the larger,oversized particles of nitrofurazone which will no pass through themedium mesh TUFCO filters. When the larger particles have been removed,the nitrofurazone/trichloroethane mixture or dispersion is combined withthe silicone rubber dispersion and agitated constantly. Preferably, thefluid mixture of the solid nitrofurazone particles in the siliconerubber dispersion is allowed to settle just prior to dipping to form therelease layer 61 on the outer surface of the overcoat layer 44 asfurther discussed herein below. It will be appreciated that thedispersion may be pumped through a single filter or a series of filtersdesigned to provide a nitrofurazone dispersion having a precise meanparticle diameter.

Referring now more specifically to the drawings, and specifically toFIGS. 1 and 2, the first step in making a balloon catheter in accordancewith the present invention is providing a double lumen tube 2, which ispreferably extruded and made of silicone rubber. It will be appreciated,however, that the double lumen tube can be made by any known processwhich yields a double lumen tube. It will be further appreciated thatthe tube can be made of any resilient polymeric material, preferably abiocompatible polymeric material which can be inserted into a human bodycavity. The double lumen tube 2 includes a smaller capillary lumen 6 anda larger fluid conduit lumen 8.

Referring now also to FIGS. 3 and 4, after the double lumen tube is cutto a desired size, a capillary lumen access opening 12 is created in anouter surface 14 of the double lumen tube 2. The capillary lumen accessopening 12 communicates with the capillary lumen 6.

Referring now also to FIGS. 5-7, an intermediate tube 3 is subsequentlyprepared from the double lumen tube 2 shown in FIG. 3. In the first stepof this process, a measured amount of a polymeric bonding composition,preferably uncured silicone rubber or another suitable polymeric bondingmaterial, is injected into the capillary lumen 6 from the distal end 16of the double lumen tube 2, so that the capillary lumen 6 is filled witha polymeric fill material 18 up to a point just below the capillarylumen access opening 12. A tip 20, preferably a rounded silicone rubbertip, is then affixed to the distal end 16 of the tube 2 to complete theformation of the intermediate tube 3 shown in FIG. 7. In a preferredmethod, the distal end 16 of the tube 2 inserted into a moldingapparatus (not shown) designed to mold a tip 20 on the end of the tube2.

Referring now also to FIGS. 7-16 and 19, a preferred process of thepresent invention involves securing a plurality of intermediate tubes 3,like the intermediate 3 shown in FIG. 7, to a rack or pallet 24. Therack or pallet 24 will include a plurality of support rods 26, eachequipped with a retaining clip 28. The intermediate tubes 3 are securedon the support rods 26 by engaging individual support rods 26 in thelarger of the two lumens, called the fluid conduit lumen 8, and slidingthe intermediate tubes 3 up over the support rods 26 until the proximalends 30 of the intermediate tubes 3 abut against the base of theretaining clips 28 or, preferably, the tip 20 of each of theintermediate tubes 3 fits snugly against the distal tip of each of thesupport rods 26, as shown in FIGS. 9 and 10. Although not shown, it isbelieved that the intermediate tubes 3 can be secured on the supportrods 26 without the aid of the retaining clips 28. This is because thepreferred extruded double lumen tubes 2 used to make the intermediatetubes 3 generally have a slight bend in one direction or another whenthey are hung. This results in a slight bend in the intermediate tubes 3that permits the intermediate tube 3 to be secured on a support rod 26without the aid of a clip 28. Because of the nature of the polymericmaterials generally used to make the intermediate tubes 3, they alsohave a tendency to cling to other surfaces and to offer resistance tomovement of a surface along a surface of this material.

When the intermediate tubes 3 have been secured on the support rods 26,the pallet 24 can be transferred from place to place, and theintermediate tubes 3 on the pallet 24 can be dipped in a series of baths(see FIG. 19) prepared to accomplish a series of process steps. In thepreferred method of the present invention, the intermediate tube 3 ismade nearly entirely of silicone rubber and is secured upon a supportrod 26 made of spring steel. The tip 20 and the fill material 18 of theintermediate tube 3 shown in FIG. 7 are made of the same material(silicone rubber) as the double lumen tube 2. Therefore, the tip 20 andthe fill material 18 form integral portions of the intermediate tube 3,which is shown in FIGS. 9-16 as an integral polymeric unit made of asingle material.

The first step in the automated coating or dipping process of formingthe balloon portion 32 of the balloon catheter 4 (shown in FIG. 13),after the intermediate tubes 3 are secured to the pallet 24, is to coatthe intermediate tubes 3 with a bond preventing agent, preferably aremovable bond preventing agent. Preferably this is accomplished bydipping each of the tubes 3 on the pallet 24 simultaneously into a firstdip tank 33 containing a bath 33a of a removable bond preventing agent,preferably a material which forms a semi-solid film on surfaces whencooled on contact followed by an opportunity for drying. Examples ofsuch materials include petroleum jelly or petrolatum, other oil basesubstances which form a semi-solid upon cooling to room temperature,liquid soaps which dry to form a semi-solid, aqueous soap or detergentsolutions, aqueous or oil based film forming solids emulsions, and thelike. In one embodiment described herein, hot petrolatum is used, and inanother, a liquid soap is used, preferably Liquid Ivory Soap fromProctor & Gamble, Cincinnati, Ohio.

When the intermediate tubes 3 are removed from this first bath 33a ofremovable bond preventing agent, the agent adheres to the outer surface14 of the intermediate tube 3, and enters the capillary lumen accessopening 12 and runs up into the capillary lumen 6. In one embodiment theagent is petrolatum, which is heated to about 140°-160° F., preferablyabout 150° F. At these temperatures, the petrolatum will run up into thecapillary lumen 6 through the capillary lumen access opening 12 with theassistance of the "capillary effect", which draws the fluid into thecapillary lumen 6 to the level of the petrolatum in the first tank 33.As the intermediate tubes 3 are withdrawn from the hot petrolatum,petrolatum on each tube cools and solidifies to form a semi-solidcoating 38 on the outer surface 14 and a semi-solid filling 34 in thecapillary lumen 6 and the capillary lumen access opening 12 whichcooperate to plug the capillary lumen access opening 12. In an alternateembodiment, the bond preventing agent in the first tank 33 is liquidsoap at room temperature (about 62°-74°) When the tubes 3 are withdrawnfrom the first dip tank 33, the liquid soap forms of semi-solid just asthe hot petrolatum did as it cooled. Although both of these bondpreventing agents are effective, there is some advantage to using thesoap because it does not require the added expense for heating.Furthermore, it is believed soap is easier to remove from the capillarylumen 6 and the balloon cavity 54.

After the intermediate tubes 3 are coated and the capillary lumen accessopenings 12 are plugged simultaneously with bond preventing agent inthis manner (see FIG. 10), the tubes 3 are then dipped in a series ofdip tanks (see FIG. 19) provided to remove the bond preventing agentfrom a portion 14a of the outer surface 14 below the dashed linedesignated B. After this portion 14a of the outer surface 14 issubstantially stripped of any residue of the bond preventing agent, theintermediate tubes 3, now partially coated with bond preventing agentbetween the dashed lines designated A and B as shown in FIG. 12, aredipped in a polymeric bonding composition, preferably silicone rubber,in a step or steps provided to coat the intermediate tube 3 to createthe balloon catheter 4 shown in FIGS. 13-14. In the preferred methods,the intermediate tube 3 is dipped in silicone rubber in two or moresuccessive dipping steps so that the resulting overcoat layer includesat least an underlying and an overlying layer, 43 and 44 respectively,which form an integral part of the balloon catheter 4 and are bondedtogether and to the outer surface 14 in the portions thereof, 14a and14b, which are located below the dashed line designated B and above thedashed line designated A, respectively. The portion 14b above line A wasnot coated prior to the final dipping steps designed to provide theovercoat layer 42, and the portion 14a below line B was stripped of itscoating prior to those steps. The balloon catheter 4 is then dipped inthe silicone rubber/nitrofurazone fluid mixture described hereinabove toform an outer bactericide release layer 61 shown in FIGS. 15 and 16.

In subsequent steps, the proximal end 30 of the balloon catheter 4 issecured to an end piece 46 to form a completed Foley catheter 5 (shownin FIG. 17). The end piece 46 can include a cap 48 for closing aproximal end access opening 49 to the fluid conduit lumen 8 and can beequipped with a luer valve 50 for engagement in and closure of theproximal capillary lumen access upper opening 52 communicating with thecapillary lumen 6. Prior to the attachment of the end piece 46 to theballoon catheter 4 to form the completed Foley catheter 5, the completedballoon catheter 4 is preferably allowed to air dry to permit solventsin the outer bactericide release layer 61 to evaporate and issubsequently cured at an elevated temperature. Care is taken to keep thecuring temperature below the boiling temperatures of the solvent so asto prevent unsightly bubbling of the solvent within the overcoat layer42 or the outer bactericide release layer 61. Because the overcoat layer42 and the outer bactericide release layer 61 are made of the samepolymeric bonding composition, even though each respective layer 42, 61may be created in a plurality of dipping steps, they are represented inFIGS. 15-18 as single layers 42, 61.

The completed Foley catheter 5 also includes a fluid conduit accessopening 56 in an exterior surface 63 of the completed Foley catheter 5.The fluid conduit access opening 56 communicates with the fluid conduitlumen 8. In preferred embodiments, the access opening 56 is punched intothe catheter 5 following the curing steps. Preferably, two accessopenings 56, one on either side of the catheter 5 (second access opening56 not shown) are punched into the catheter 5. In an alternateembodiment (not shown), the access opening 56 is created before theintermediate tube 4 is dipped in the silicone bactericide coatingmixture (silicone/nitrofuran compound fluid mixture). In thisembodiment, an inner surface layer (not shown), incorporating thebactericide agent 15 is created along an inside of the fluid conduitlumen 8.

In preferred methods in accordance with the present invention, the endpiece 46 is made by a process of injection molding. Preferably, theproximal end 30 of the balloon catheter 4 is inserted into the injectionmolding apparatus after the overcoat layer 42 and the release layer 61have been cured. The polymeric bonding composition, preferably siliconerubber, is then injected into the mold (not shown) and the end piece 46is molded onto the proximal end 30 of the balloon catheter 4 to make thecompleted Foley catheter 5 shown in FIG. 17. Following further dryingcuring steps where deemed necessary given the type of polymeric bondingcomposition or compositions used to make the completed Foley catheter 5,the completed catheter 5 is tested to see if it is functional and if ithas any leaks. This testing can be done before or after the fluidconduit access opening 56 is created in the exterior surface 62 tocommunicate with the fluid conduit lumen 8. Care is taken during suchtesting to avoid any needless exposure of the release layer 61 or anyother nitrofuran impregnated natrices to aqueous environments.

In order to test the integrity of the completed catheter 5, prior toengaging the plug 50 in the proximal capillary lumen access opening 52in the end piece 46, the proximal capillary lumen access opening 52 isslipped over a hot water nozzle (not shown), and a measured amount of ahot aqueous solution, preferably water or water containing a trace ofsurfactant, at a temperature of between about 120°-160° F., preferablyabout 140° F., is pumped into the capillary lumen 6 from a standard hotwater heater (not shown) by a commercially available water pump (notshown) such that the balloon portion 58 is expanded. The balloon portion58 of the overcoat layer 42 is the portion of the overcoat layer 42which is not bonded to the outer surface 14 of the intermediate tube 3.The balloon portion 58 of the overcoat layer 42 cooperates with theportion 14c of the outer surface 14 which remained coated with the bondpreventing agent prior to the step of dipping the intermediate tube 3 inthe polymeric bonding composition, to define a balloon cavity 54. Theballoon cavity 54 communicates with the capillary lumen 6 via thecapillary lumen access opening 12. When the hot water solution is pumpedor injected into the capillary access lumen 6 to test the completedcatheter 5 and the balloon portion 58, the balloon portion 58 and theballoon cavity 54 are expanded. If there is a significant lack ofintegrity in the balloon portion 58 it will be exposed when the water isintroduced in this manner. In addition to testing the balloon portion58, the water solution will also remove the remaining bond preventingagent in the balloon lumen 54 and the capillary lumen 6 when it isremoved. Although some of the bond preventing agent may come out of thecapillary lumen 6 via the proximal capillary lumen access opening 52during the step of curing the overcoat layer 42, the hot aqueoussolution is generally believed to remove most of the bond preventingagent, although a residue may remain.

Following the preliminary test, which relies on a visual observation todetermine whether there is any lack of integrity, a further test is usedto obtain further assurance that there are no leaks in the balloonportion 58. This further test is accomplished by engaging the proximalcapillary lumen accessing opening 52 to the nozzle of a commerciallyavailable leak tester (not shown). One such device is a Model No. 6510Caps Tester from Caps Himmelstein (Hoffman Estates, IL 60195). Once thecompleted catheter 5 is tightly secured over the nozzle, an electricalswitch, such as a hand switch or, preferably, a foot pedal, is used torelease a measured blast of air into the capillary lumen 6. When the airis introduced into the capillary lumen 6 it also enters the ballooncavity 54 via the capillary lumen access opening 12 and inflates theballoon portion 58 and, thereby, expands the balloon cavity 54. The leaktester is designed to sense any loss of pressure once the balloonportion 58 is inflated, and will given an indication, therefore, ifthere are any measurable leaks. After this test is completed, thecompleted catheters 5 that have passed all tests, are then packaged,preferably in a material which breathes such as Tyvek™ (from DuPont),and boxed. The boxes are then sterilized with ETO (ethylene oxide) andthen stored for shipment.

In the Applicants' use of the preferred methods of the presentinvention, balloon fabrication is almost completely automated. Entiresets of balloon catheters 4 are manufactured simultaneously. Thepreferred pallet 24 has 400 spring steel support rods 26 attached to apallet in 20 rows of 20 rods, wherein each of the rods 26 is about 1inch from each adjacent rod. Double lumen tubing (not shown) ispreferably made by an extrusion process which is known to those of skillin the art. The tubes 2 are cut to length as the tubing leaves theextruder (not shown). An opening 12 is created in the outer surface 14,preferably with a hollow drill bit or tube (not shown), so as tocommunicate with the capillary lumen 6. The distal portion 6a of thecapillary lumen 6, located between the distal end 16 of the tube 2 andthe capillary lumen access opening 12, is injected with a measuredamount of a polymeric bonding composition, preferably silicone rubber,so that the distal portion 6a is filled and sealed. A rounded tip 20 ispreferably formed at the distal end 16 of the double lumen tube 2 byinserting the tube 2 in a molding device (not shown).

In one embodiment of the present method, 400 of the intermediate tubes 3are then mounted vertically on rigid spring steel support rods 26 on apallet 24 in the manner previously described. The pallet 24 is thenmoved via a transporting mechanism 22 (see FIG. 19) over a series of diptanks as follows in one of these embodiments:

(A) The pallet 24 is stopped over a first tank 33, which contains whiteUSP petrolatum heated to about 67° C. (about 150° F.). The tank israised so as to immerse the intermediate tubes 3 into the petrolatum tosuch a depth that the petrolatum reaches the proximal end of the desiredballoon location. The dip tank 33 is then lowered and a portion of theouter surface 14 of the intermediate tubes 3 are coated with petrolatum.This portion extends from the point at which the proximal end of theballoon portion 58 will begin to the distal end of the tip 20 of theintermediate tube 3.

(B) The pallet 24 is then automatically advanced and stopped over asecond dip tank 35 which contains white USP petrolatum heated to about120° C. (about 250° F.). The second dip tank 35 is raised so as toimmerse the intermediate tubes 3 into the super-heated petrolatum sothat the super-heated petrolatum comes into contact with the petrolatumcoating on outer surface 14 of the intermediate tube 3 from the priordipping step up to a location where a distal end of the balloon portion58 will end. The second dip tank 35 is then lowered. This dipping stepcauses the coating of petrolatum from the prior dipping step to belargely removed from a portion 14a of the outer surface 14 of theintermediate tube 3 from a location where the distal end of the balloonlumen 54 will be located (designated by dashed line B) to the distal end20a of the tip 20 of the intermediate tube 3. Some residual petrolatummay remain on the outer surface 14 of the intermediate tube 3 in thisportion 14a of the outer surface 14. However, most of the petrolatum isremoved.

(C) The pallet 24 is then automatically advanced and stopped over athird dip tank 37 containing mineral spirits heated to about 200° F. Thethird dip tank 37 is then raised so as to immerse the intermediate tubes3 into the mineral spirits to the same depth as they were immersed inthe super-heated petrolatum in the second dip tank 35. The tank 37 isthen lowered and all but a trace amount of the petrolatum is removedfrom the portion 14a of the outer surface 14 below the portion 14c ofthe outer surface 14, which will eventually be proximate the balloonlumen 54.

(D) The pallet 24 is then automatically advanced and stopped over afourth dip tank 39 containing a volatile organic solvent such astoluene, trichloromethane or the like. The fourth tank 39 is then raisedto immerse the intermediate catheters 3 to the same depth as previouslyimmersed in the second and third tanks 35 and 37, thereby removingessentially all traces of the petrolatum from this portion 14a of theouter surface 14. The intermediate catheter tube 3 now has a band 38 ofsemi-solid petrolatum located around the axial circumference of theintermediate tube 3 in the location where the balloon cavity 54 will becreated. The petrolatum not only coats the portion 14c of the outersurface 14 located in this area, but also fills a portion of thecapillary lumen 6 and plugs the capillary lumen access opening 12, whichwill eventually be used to inflate the balloon portion 58 of thecompleted Foley catheter 5.

(E) The pallet 24 is then lowered and automatically advanced to a fifthdip tank 41 containing a low-solids hexamethyl disiloxane or toluenesilicone rubber solution which is effective to minimize any disruptionof the integrity of the petrolatum coating 38 remaining on theintermediate tube 3 proximate the portion 14c of the outer surface 14where the balloon lumen 54 will be created during subsequent dippingsteps. The fifth tank 41 is then raised to immerse essentially theentire length of the intermediate tube 3 in the solution. This step canbe subsequently repeated at intervals, preferably allowing time forsignificant solvent evaporation, either in the same tank or in asubsequent tank containing a greater concentration of silicone rubber,until the overcoat layer 42 and the balloon portion 58 of the overcoatlayer 42 have a desired balloon thickness. The preferred thickness overthe overcoat layer 42 and the balloon portion 58 is 17.5 thousandths ofan inch (plus or minus 2.5 thousandths of an inch). The tank 41 is thenlowered, and the overcoat layer 42 is allowed to dry and the solvent isallowed to evaporate for about 15 minutes, preferably about 30 minutes,even more preferably about an hour.

(F) The pallet 24 is advanced to a sixth dip tank 43 containing asilicone rubber/nitrofuran compound mixture or dispersion 17, and thetubes 3 are completely immersed again. The tank 43 is lowered. Thepallet is then advanced through a drying area where solvents are allowedto evaporate, and then through a heat cure step, where the ballooncatheters 4 formed by this process are cured at a temperature just belowthe boiling point of any solvent used in any of the silicone rubber dipsolutions for an hour or two. For toluene this temperature is about 200°F.

(G) After the heat cure, the balloon catheters 4 are allowed to cool andare then removed from the support rods 26. The proximal ends 30 of eachof the balloon catheters 4 is then inserted into an injection moldingapparatus (not shown), which forms the end piece 46 of the completedFoley catheter 5.

(H) The completed Foley catheters 5 are then finished by punching afluid conduit access opening 56 in the exterior surface 62 such that itcommunicates with the fluid conduit lumen 8 in a location below ordistal to the balloon portion 58.

(I) The completed Foley catheters 5 are then sent through the testsequence described hereinabove, during which the balloon portion 58 ofeach completed Foley catheter 5 is inflated and the petrolatum band 38within the balloon cavity 54 is largely removed.

Referring now to FIGS. 20a, 20b and 20c, the present invention providesa method of making balloon catheters including the following steps:

(A) Providing a tube having an outer surface and first and secondlumens;

(B) Cutting the tube to a desired length;

(C) Creating a first lumen access opening in the outer surface tocommunicate with the first lumen;

(D) Filling the first lumen with a polymeric bonding composition up tothe first lumen access opening from an end nearest the first lumenaccess opening;

(E) Sealing the end of the tube nearest the first lumen access opening;and

(F) Securing the tube to a movable pallet.

These steps are followed by the following steps:

(A) Simultaneously coating a first portion of the outer surface andplugging the first lumen access opening with a removable bond preventingagent;

(B) Stripping the coating of removable bond preventing agent away from aportion of the outer surface adjacent to the first portion;

(C) Coating the outer surface and the remaining coating of removablebond preventing agent with an overcoat layer of a suitable film formingpolymeric bonding composition;

(D) Coating the overcoat layer with a silicone rubber/bactericidecoating mixture to form an outer bactericide release layer;

(E) Air drying outer bactericide release layer; and

(F) Curing the overcoat layer and the outer bactericide release layer.

Following those steps, methods of the present invention include thefollowing steps:

(A) Securing an end piece to the end of the tube furthest from the firstlumen access opening;

(B) Simultaneously testing the balloon portion of the resulting catheterand substantially removing the removable preventing bond agent from thefirst portion of the outer surface and the first lumen access opening;

(C) Further testing the catheter capillary lumen and the balloon portionfor leaks;

(D) Punching a second lumen access opening in an exterior surface of thecatheter to communicate with the second lumen;

(E) Packaging the resulting balloon catheters; and

(F) Sterilizing the balloon catheters.

In preferred embodiment of the present invention following the securingof a plurality of intermediate tubes 3 to the transportable pallet 24,balloon catheters are produced as follows:

(A) The pallet 24 is stopped over a first tank 33, which contains aliquid soap (Liquid Ivory Soap from Proctor & Gamble Co., Cincinnati,Ohio 45202). The soap is held at room temperature (between about 60°-80°F., preferably 65°-72° F.). The dip tank 33 is raised so as to immersethe intermediate tubes 3 into the liquid soap so that the soap coats thetubes 3 up to the dashed line designated by the letter A in FIG. 10. Thedip tank 33 is then lowered and the liquid soap forms a semi-solidcoating 38 on the outer surface 14 of each of the intermediate tubesextending from line A to the distal end of the tip 20 of theintermediate tubes 3.

(B) The pallet 24 is then automatically advanced and stopped over asecond dip tank 35 which contains an aqueous solution containing a traceof a suitable wetting agent or surfactant. In a preferred embodiment,three gallons of water is mixed with two ounces of a suitablesurfactant. The surfactant will generally be less than one percent ofthe total volume of the solution. The second dip tank 35 is then raisedso as to immerse the intermediate tubes 3 in the aqueous fluid up to thedashed line designated by the letter B in FIGS. 10 and 12. The seconddip tank 35 is then lowered and the semi-solid liquid soap coating theportion 14a of the outer surface 14 below the dashed line designated Bis substantially removed.

(C) The pallet 24 is then automatically advanced and stopped over athird dip tank 37 containing water. The third dip tank 37 is then raisedand the intermediate tubes are immersed in the water up to the linedesignated B as in the prior dipping step. The third dip tank 37 is thenlowered and virtually all of the liquid soap is removed from the portion14a of the outer surface 14 below the line designated B.

(D) The pallet 24 is then automatically advanced and stopped over afourth dip tank 39 containing a low-solids hexamethyl disiloxanesilicone rubber solution which is effective to minimize any disruptionof the integrity of the liquid soap coating 38 remaining on each of theintermediate tubes proximate the portion 14c of the outer surface 14where the balloon lumen will be created during subsequent dipping steps(the portion between the dashed lines designated A and B). The fourthtank 39 is then raised to immerse essentially the entire length of eachof the intermediate tubes 3 in the silicone rubber solution. It will beappreciated that other organic solvents such as toluene, and the likemay be substituted for the hexamethyl disiloxane solvent used in thisexample. It will also be appreciated that the dipping step can berepeated at subsequent intervals, preferably long enough to permitsignificant solvent evaporation (prior to any subsequent dipping), toadd to the thickness of the overcoat layer 42 and the balloon portion 58of the overcoat layer 42. Further steps, involving different solutions,can also follow.

(E) Once the fourth dip tank 39 is lowered, and the uncured siliconerubber, coating portions of the outer surface 14 as well as the coatingof soap 38, is allowed to dry, the pallet 24 is advanced again to afifth dip tank 41 preferably containing a different silicone rubbersolution having a solids content which is higher than the solids contentin the fourth dip tank 39. This step can be eliminated, but may beuseful to add thickness if desired. The intermediate tubes are immersedagain in the subsequent silicone rubber solution when the fifth dip tank41 is raised. The fifth dip tank 41 is then lowered, and the siliconerubber coating the tubes 3 is allowed to dry.

(F) The pallet 24 is then automatically advanced again to a sixth diptank 43 containing the silicone rubber/nitrofuran compound fluid mixturedescribed hereinabove. The tubes can be dipped a second time afterallowing about 10-15 minutes for drying. The sixth dip tank 43 is thenlowered and the silicone rubber/nitrofuran compound coating the tubes 3is allowed to dry for about 15 minutes.

(G) The pallet 24 is then advanced through a drying step followed by aheat cure step (air dried at 200° F. for 1 hour), and each completedballoon catheter 4 is then secured to an end piece, tested, providedwith a fluid conduit access opening 56, packaged and sterilized.

The automated system that Applicants claim will permit completed Foleycatheters 5 to be manufactured at the rate of about 1,600 catheters perhour. Because no handwork is involved, the catheters 5 produced will beconsistent and of very high quality. The exterior surface 62 is smootherthan hand-glued balloons, and the outside diameter of the balloonportion 58 is essentially identical to the outside diameter of otherportions of the completed Foley catheters 5. In addition, by eliminatingthe hand labor involved in adhering the balloon portion 58 to theintermediate tube 3 in the manufacture of silicone rubber ballooncatheters 4, by specifically eliminating the separate step offabricating the balloon portion, which also requires hand labor, and byeliminating the significant impact on yield resulting from handprocessing errors, the applicants' new process will permit directproduction cost for silicone rubber balloon catheters of all types to bereduced by about 25-50% over the cost estimated for the prior artsilicone rubber balloon catheters.

Referring now also to FIGS. 21-38, to FIGS. 21 and 22, the first step inmaking an alternate balloon catheter 4' in accordance with the presentinvention is providing a double lumen tube 2', which is preferablyextruded and made of silicone rubber. It will be appreciated, however,that the double lumen tube 2' can be made by any known process whichyields a double lumen tube 2'. It will be further appreciated that thetube 2' can be made of any resilient polymeric material, preferably abiocompatible polymeric material which can be inserted into a human bodycavity. The double lumen tube 2' includes a smaller capillary lumen 6'and a larger fluid conduit lumen 8'.

Referring specifically now also to FIGS. 23 and 24, after the doublelumen tube 2' is cut to a desired size, a capillary lumen access opening12' is created in an outer surface 14' of the double lumen tube 2'. Thecapillary lumen access opening 12' communicates with the capillary lumen6'.

Referring specifically now also to FIGS. 25-27, an intermediate tube 3'is subsequently prepared from the double lumen tube 2' shown in FIG. 9.In the first step of this process, a measured amount of a polymericbonding composition, preferably silicone rubber or another suitablepolymeric bonding material, is injected into the capillary lumen 6' fromthe distal end 16' of the double lumen tube 2', so that the capillarylumen 6' is filled with a polymeric fill material 18' up to a point justbelow the capillary lumen access opening 12'. A tip 20', preferably arounded silicone rubber tip, is then affixed to the distal end 16' ofthe tube 2' to complete the formation of the intermediate tube 3' shownin FIG. 13. In a preferred method, the distal end 16' of the tube 2' isinserted into a molding apparatus (not shown) designed to mold a tip 20'on the end of the tube 2'.

Referring now also to FIGS. 28-36 and 41, a preferred process of thepresent invention involves securing a plurality of intermediate tubes3', like the intermediate tube 3' shown in FIG. 13, to a rack or pallet24'. The rack or pallet 24' will include a plurality of support rods26', each equipped with a retaining clip 28'. The intermediate tubes 3'are secured on the support rods 26' by engaging individual support rods26' in the larger of the two lumens 8', called the fluid conduit lumen8', and sliding the intermediate tubes 3' up over the support rods 26'until the proximal ends 30' of the intermediate tubes 3' abut againstthe base of the retaining clips 28' or, preferably, the tip 20' of eachof the intermediate tubes 3' fits snugly against the distal tip 26a' ofeach of the support rods 26', as shown in FIGS. 29 and 30. Although notshown, it is believed that the intermediate tubes 3' can be secured onthe support rods 26' without the aid of the retaining clips 28'. This isbecause the preferred extruded double lumen tubes 2' used to make theintermediate tubes 3' generally have a slight bend in one direction oranother when they are hung. This results in a slight bend in theintermediate tubes 3' that permits the intermediate tube 3' to besecured on a support rod 26' without the aid of a clip 28'. Because ofthe nature of the polymeric materials generally used to make theintermediate tubes 3', they also have a tendency to cling to othersurfaces and to offer resistance to movement of a surface along asurface of this material as do most polymeric tubes including thosetubes 2 described hereinabove.

When the intermediate tubes 3' have been secured on the support rods26', the pallet 24' can be transferred from place to place, and theintermediate tubes 3' on the pallet 24' can be dipped in a series ofbaths prepared to accomplish a series of process steps. In the preferredmethod of the present invention, the intermediate tube 3' is madeentirely of silicone rubber and is secured upon a support rod 26' madeof spring steel. The tip 20' and the fill material 18' of theintermediate tube 3' shown in FIG. 27 are made of the same material(silicone rubber) as the double lumen tube 2'. Therefore, the tip 20'and the fill material 18' preferably form integral portions of theintermediate tube 3', which is shown in FIGS. 29-36.

The first step in the automated coating or dipping process of formingthe resilient sleeve 44' and the balloon portion 32' of the ballooncatheter 4' (shown in FIG. 36), after the intermediate tubes 3' aresecured to the pallet 24', is to coat the intermediate tubes 3' with abond preventing lubricating agent or substance 38', preferably aremovable bond preventing lubricating agent. Preferably this isaccomplished by dipping each of the tubes 3' on the pallet 24',simultaneously into a first dip tank 33' containing a bath 33a' of aremovable bond, preferably a material which forms a semi-solid film onsurfaces when cooled on contact followed by an opportunity for drying.Examples of such materials include petroleum jelly or petrolatum, otheroil base substances which form a semi-solid upon cooling to roomtemperature, liquid soaps which dry to form a semi-solid, aqueous soapor detergent solutions, aqueous or oil based film forming solidsemulsions, and the like. In one embodiment described herein, hotpetrolatum is used, and in another, a liquid soap is used, preferablyLiquid Ivory Soap from Proctor & Gamble, Cincinnati, Ohio.

When the intermediate tubes 3' are removed from this first bath 33a' ofremovable bond preventing lubricating agent 38', the agent or substance38' adheres to the outer surface 14' of the intermediate tube 3', andoccupy the capillary lumen access opening 12' and the capillary lumen6'. In one embodiment the agent is petrolatum, which is heated to about140°-160° F., preferably about 150° F. At these temperatures, thepetrolatum will run up into the capillary lumen 6' through the capillarylumen access opening 12' with the assistance of the "capillary effect",which draws the fluid into the capillary lumen 6' to the level of thepetrolatum in the first tank 33'. As the intermediate tubes 3' arewithdrawn from the hot petrolatum, petrolatum on each tube cools andsolidifies to form a semi-solid coating 38' on the outer surface 14' anda semi-solid filling (not shown) in the capillary lumen 6' and thecapillary lumen access opening 12' which cooperate to plug the capillarylumen access opening 12'. In an alternate embodiment, the bondpreventing agent in the first tank 33' is liquid soap at roomtemperature (about 62°-74° F.). When the tubes 3 are withdrawn from thefirst dip tank 33, the liquid soap forms a semi-solid just as the hotpetrolatum did as it cooled.

In the preferred method of the present invention, the intermediate tubes3' are coated when they are dipped in a first bath 33a' which containspetrolatum which is maintained at a temperature effective to permit thepetrolatum to coat the outer surface 14' of the tube while limiting thedegree to which the petrolatum runs into the smaller lumen 6'. Thepetrolatum will run into the first lumen access opening 12', but,preferably, will not run very far into the smaller lumen 6'. Thetemperature of the petrolatum in the first tank 33' is preferablymaintained at about 40°-80°, more preferably about 50°-70°, even morepreferably about 55°-65°, and most preferably about 60° C. for thispurpose. As shown in FIG. 29, the intermediate tube 3' is coated withthe bond preventing lubricating agent 38' up to a location on thesurface 14' of the intermediate tube 3' proximate the dashed line Ashown in FIG. 29 by dipping the intermediate tube 3' into the first diptank 33' up to that point.

Following this step, the outer surface 14' of the intermediate tube 3'is stripped of the bond preventing lubricating agent 38' up to alocation proximate the dashed line designated B in FIGS. 29 and 30. Thisis preferably accomplished by one or more dipping steps in accordancewith the methods for stripping particular lubricating agents asdescribed hereinbelow. The intermediate tube is then preferably coatedas shown in FIG. 30 between the locations proximate the dashed lines Aand B. The intermediate tube 3' shown in FIG. 30 is then dipped in asubsequent dip tank holding a second bond preventing agent. In this stepthe liquid soap can be preferred, although petrolatum and other agentswill also work. During this step, the intermediate tube 3' shown in FIG.30 is dipped into the tank up to a point on the outer surface 14' of theintermediate tube 3' proximate the dashed line C so as to coat theportion of the intermediate tube 3' from the lowest portion of the tip20' up to the location proximate the dashed line designated C. Inpreferred embodiments of the present invention, any of the bondpreventing lubricating agents enumerated above may be used. Preferably,however, the bond preventing lubricating agent is hot petrolatum heatedto about 130°-150° F., preferably about 140° F. (about 60° C.), orliquid soap at room temperature (about 62°74° F.). When the intermediatetubes 3' are withdrawn from the hot petrolatum, petrolatum will cool andsolidify to form a semi-solid coat 39' on the outer surface 14' and asemi-solid filling 34' in the capillary lumen 6' and the capillary lumenaccess opening 12' which cooperate to plug the capillary lumen accessopening 12' as shown in FIG. 32. As stated above, soap at roomtemperature will provide the same function as the petrolatum. Theintermediate tube is then subjected to a further dipping step whereinthe intermediate tube shown in FIG. 32 is dipped in one or more diptanks so as to strip the coating of bond preventing agent 39' from theportion of the intermediate tube 3' below a location on the outersurface 14' proximate the dashed line designated D in FIGS. 32 and 33 soas to strip the tube of bond preventing agent below that location.

After the intermediate tubes 3' are coated in this manner and thecapillary lumen access openings 12' are plugged with bond preventingagent 40', the tubes 3' are then dipped in a series of dip tanks (seeFIG. 41) provided to coat the intermediate tube 3' with a polymericbonding composition, preferably silicone rubber, in a step or stepsprovided to form the overcoat layer 42', and, following a short dryinginterval, an outer bactericide release layer 61' is created by dippingthe intermediate tube 3' into the silicone rubber/nitrofuran compoundmixture or dispersion 17 in the last dip tank 57'. The outer releaselayer 61' is then air dried for about an hour, and then cured. In orderto avoid a poor bond between the release layer 61' and the rest of thetube 3', the release layer 61' is coated only over the uncured siliconerubber overcoat layer 42'. In order to avoid any sagging, elongation orstretching of the resilient sleeve 44' or the balloon portion 58' of theballoon catheter 5' shown in FIG. 35. The catheter 4' is cured in a hotliquid bath at 160° F. for about 15 min., and then cured in hot air at200° F. for an additional hour. This prevents the sleeve from droopingwhen the contents of the sleeve are raised to high temperatures. In thepreferred methods, the intermediate tube 3' is dipped in silicone rubberin two or more successive dipping steps so that the resulting overcoatlayer 42' includes underlying and an overlying layers (not shown), whichform an integral part of the balloon catheter 5' and are bondedtogether, and to the outer surface 14' in the portions thereof, 14a',14b' and 14d', which are located below the dashed line designated D,between the dashed lines designated B and C, and above the dashed linedesignated A, respectively. The portion 14d' above line A was not coatedprior to the final dipping steps designed to provide the overcoat layer42', and the portion 14a' below line D was stripped of its coating priorto those steps.

In subsequent steps, the proximal end 30' of the balloon catheter 5' issecured to an end piece 46' to form a completed Foley catheter 4' (shownin FIG. 38). The end piece 46' can include a cap 48' for closing aproximal end access opening 49' to the fluid conduit lumen 8' and can beequipped with a luer valve 50' for engagement in and closure of theproximal capillary lumen access upper opening 52' communicating with thecapillary lumen 6'. Prior to the attachment of the end piece 46' to thesleeved balloon catheter 5' to form the completed sleeved Foley catheter4', the sleeved balloon catheter 5' is preferably allowed to air dry topermit solvents in the overcoat layer 42' to evaporate and issubsequently cured at an elevated temperature. Care is taken to keep thecuring temperature below the boiling temperatures of the solvent so asto prevent unsightly bubbling of the solvent within the overcoat layer42'. Because the overcoat layer 42' is preferably made of the samepolymeric bonding composition, even though it may be created in aplurality of dipping steps, it is represented in FIGS. 35-39 as a singleovercoat layer 42'. It will be appreciated, however, that this singleovercoat layer 42' may or may not represent an integral layer formed ina series of dipping steps wherein there may be any number of underlyingor overlying layers. The completed Foley catheter 4' also includes afluid conduit access opening 56' in an exterior surface 62' of thecompleted Foley catheter 4'. The fluid conduit access opening 56'communicates with the fluid conduit lumen 8'.

Referring now also to FIG. 37, the independence and stretchability ofthe resilient sleeve 44' is illustrated. The resilient sleeve 44', whichincludes goth the overcoat layer 42' and the release layer 61', not onlyhas a narrower thickness than the inner wall 21' of the catheter 5', butit is also more flexible, more stretchable, and preferably less rigidthan the inner wall 21'. The lubricating substance 38' contained in thesleeve cavity 45' permits the sleeve 44' to slide along and in respectto the outer surface 14' while in lubricated contact therewith and whenstretched independently thereof. As illustrated in FIG. 37, theresilient sleeve 44' can be twisted in respect to the inner wall 21'without twisting the inner wall 21' or the respective lumens, 6' and 8'.The resilient sleeve 44' can also be stretched without stretching theinner wall 21' of the catheter 5'. As stated hereinabove, this enablesthe resilient sleeve 44' to stay in relative contact with or inadherence to adjacent body tissues (not shown) with which the resilientsleeve 44' is in contact with even when the remaining portions of thesleeved balloon catheter 5', such as the inner wall 21', are forced tomove in response to forces impacting on the catheter 5' at other pointsalong its length. The resilient sleeve 44 can also change from itsinitial circumferential shape to a more ribbon-like oval shape in orderto match the shape or contour of the passageway in which it resides. Thevolume of the sleeve cavity 45' will preferably increase the outsidediameter of the catheter proximate the sleeve portion at least about 5%,preferably about 10%, more preferably about 20%, even more preferablyabout 25 %, even more preferably about 35%, and even more preferablyabout 50%. It is conceivable that applications will also be found wherethe thickness of the lubricating substance in the sleeve cavity 45 isincreased so as to increase the volume of the sleeve cavity such thatthe outside diameter of the catheter proximate the sleeve 44 will beincreased from about 50 to 100, or 50 to 200% or more depending on theparticular application. The important factor is that the sleeve be softand compliant so that it can conform to the shape of the particularpassageway in which it resides and, at the same time fill the passagewayso as to limit the passage of fluids along either the wall of thepassageway or the exterior surface of the catheter, and at the sametime, to allow the inner conduit portion of the catheter move relativelyindependently of the exterior surface of the sleeve 44' of the catheter.

In preferred methods in accordance with the present invention, the endpiece 46' is made by a process of injection molding. Preferably, theproximal end 30' of the sleeved balloon catheter 5' is inserted into aninjection molding apparatus (not shown) after the overcoat layer 42' andthe release layer 61' have been cured. However, it will be appreciatedthat the end piece 46' can be added to the intermediate tube 3' prior tothe initiation of the dipping process. A polymeric bonding composition,preferably silicone rubber, is then injected into the mold (not shown)and the end piece 46' is molded onto the proximal end 30' of the ballooncatheter 5' to make the completed Foley catheter 4' shown in FIG. 38.Following further drying, curing steps, where deemed necessary given thetype of polymeric bonding composition or compositions used to make thecompleted Foley catheter 4', the completed catheter 4' is tested to seeif it is functional and if it has any leaks. This testing can be donebefore or after the fluid conduit access opening 56' is created in theexterior surface 62' to communicate with the fluid conduit lumen 8'.

In order to test the integrity of the completed catheter 4', prior toengaging the plug 50' in the proximal capillary lumen access opening 52'in the end piece 46', the proximal capillary lumen access opening 52' isslipped over a hot water nozzle (not shown), and a measured amount of ahot aqueous solution, preferably water or water containing a trace ofsurfactant, at a temperature of between about 120°-160° F., preferablyabout 140° F., is pumped into the capillary lumen 6' from a standard hotwater heater (not shown) by a commercially available water pump (notshown) such that the balloon portion 58' is expanded. It will beappreciated that higher or lower temperatures can be used so long as thedesired coating properties for the particular application desired can beobtained. The balloon portion 58' of the overcoat layer 42' is theportion of the overcoat layer 42' which is not bonded to the outersurface 14' of the intermediate tube 3' proximate a balloon cavity 54'.The balloon portion 58' of the overcoat layer 42' cooperates with theportion 14c' of the outer surface 14' which remained coated with thebond preventing agent prior to the step of dipping the intermediate tube3' in the polymeric bonding composition, to define the balloon cavity54'. The balloon cavity 54' communicates with the capillary lumen 6' viathe capillary lumen access opening 12'. When the hot water solution ispumped or injected into the capillary access lumen 6' to test thecompleted catheter 4' and the balloon portion 58', the balloon portion58' and the balloon cavity 54' are expanded. If there is a significantlack of integrity in the balloon portion 58' it will be exposed when thewater is introduced in this manner. In addition to testing the balloonportion 58', the water solution will also remove the remaining bondpreventing agent in the balloon lumen 54' and the capillary lumen 6'when it is removed. Although some of the bond preventing agent may comeout of the capillary lumen 6' via the proximal capillary lumen accessopening 52' during the step of curing the overcoat layer 42', the hotaqueous solution is generally believed to remove most of the bondpreventing agent, although a residue may remain.

Following the preliminary test, which relies on a visual observation todetermine whether there is any lack of integrity, a further test is usedto obtain further assurance that there are no leaks in the balloonportion 58. This further test is accomplished by engaging the proximalcapillary lumen accessing opening 52' to the nozzle of a commerciallyavailable leak tester (not shown). One such device is a Model No. 6510Caps Tester from Caps Himmelstein (Hoffman Estates, IL 60195). Once thecompleted catheter 4' is tightly secured over the nozzle, an electricalswitch, such as a hand switch or, preferably, a foot pedal, is used torelease a measured blast of air into the capillary lumen 6'. When theair is introduced into the capillary lumen 6' it also enters the ballooncavity 54' via the capillary lumen access opening 12' and inflates theballoon portion 58' and, thereby, expands the balloon cavity 54'. Theleak tester is designed to sense any loss of pressure once the balloonportion 58' is inflated, and will given an indication, therefore, ifthere are any measurable leaks. After this test is completed, thecompleted sleeved Foley catheters 4' that have passed all tests, arethen packaged, preferably in a material which breathes such as Tyvek™(from DuPont), and boxed. The boxes are then sterilized with ETO(Ethylene Oxide) and then stored for shipment.

Referring now specifically to FIGS. 43-49, the present inventionprovides an elongated catheter 4'" (see FIG. 49) having an interiorsurface 7'" and an exterior surface 9'". The interior surface 7'"defines a lumen 8'". The elongated catheter 4'" is preferably made froma tube 2'" (see FIG. 43) which is eventually coated with an overcoatlayer 42'" of a resilient polymeric material which binds to an outersurface 14'" of the tube 2'" unless the bonding of the polymericmaterial is prevented by other materials or means on the outer surface14'".

The overcoat layer 42 of the elongated catheter 4'" in accordance withthe present invention, includes a sleeve 44'" which encircles a sleevecavity 45'" which contains lubricating material 38'". The lubricatingmaterial or substance 38'" is effective to permit the sleeve 44'" toslide along the outer surface 14'" of the tube 2'" proximate the sleeve44'" while in lubricated contact with the outer surface 14'". Whenapplied in sufficient thicknesses, the lubricating material serves toseparate the soft outer sleeve 44'" from the tube 2'", such that theouter sleeve 44'" provides a soft, cushioned, compliant exterior surfacewhich can adapt and conform under slight pressures to the shape of thepassageway in which it is inserted or residing. Depending on thecatheter application and/or type, the amount of the lubricatingsubstance 38'" and the sleeve cavity 45'" can be minimized to providefor only a limited increase in the outer diameter of the catheterproximate the outer sleeve 44'". The outer sleeve 44'" is coated with anouter bactericide release layer 61'" similar to that describedhereinabove. In other cases, a soft, cushioned, compliant sleeve whichcan adapt its shape is desirable. In these embodiments, there is arelatively thick coating of lubricant material 38'" in the sleeve cavity45'" which will give the sleeve 44'" a balloon-like feel and appearancein the exterior surface proximate the sleeve 44'". The elongatedcatheter 4'" is preferably made of a flexible elastomeric material suchas latex, silicone rubber or the like, most preferably silicone rubber.The lubricating material or substance 38'" is preferably anybiocompatible lubricating substance which is effective to permitrespective polymeric surfaces to slide with respect to one another whenin lubricated contact therewith. Preferably, the lubricating substance38'" is a hydrophobic oil or other petroleum based product or awater-soluble soap, detergent or the like, either of which is effectiveto lubricate polymeric surfaces and to generally prevent bonding theretoby other polymeric substances when coated thereby. In a preferredembodiment, the lubricating substance 38'" is petrolatum.

The first step in making an elongated catheter 4'" in accordance withthe method of the present invention is to provide a tube 2'" having anouter surface 14'" and an inner surface 7'" defining a first lumen 8'".The distal end 16'" of the tube 2'" is preferably inserted into amolding apparatus (not shown) designed to mould a tip 20'" on the distalend 16'" of the tube 2'" to form the intermediate tube 3'" (see FIG.44). In a preferred process of the present invention, the intermediatetube 3'" is then secured on a support rod 26'" of a rack or pellet 24'"which preferably includes a plurality of support rods 26'". Preferably,a plurality of intermediate tubes 3'" are secured on the plurality ofsupport rods prior to subjecting the intermediate tubes 3'" secured onthe support rods 26'" to a series of dipping steps in the preferredprocess.

After the intermediate tube 3'" is formed from the initial tube 2'", theouter surface is coated from the lowest portion of the tip 20'" up to alocation on the outer surface 14'" designated by the dashed line A, asshown in FIG. 45, with the lubricating substance. Subsequently, thelubricating substance coating the outer surface 14 of the tube below alocation proximate the dashed line designated B, as shown in FIGS. 45and 46, is stripped from the outer surface 14'" and the tip 20'". Theintermediate tube 3'" is then coated with a resilient polymeric bondingcomposition which forms the overcoat layer 42'". The overcoat layer 42'"bonds to the tip 20'" and a portion of the outer surface 14a'" below thedash line designated B, and to a portion of the outer surface 14b'"above the line designated A. In the area proximate to a portion of theouter surface 14c'" between the dash lines designated A and B,respectively, which remains coated with lubricating material 38'", theovercoat layer 42'" forms a sleeve 44'" which encircles the lubricatingmaterial 38'" coating the portion of the outer surface 14a'" between thedash lines designated A and B, which cooperates with the sleeve 44'" todefine the sleeve cavity 45'" in which the lubricating material 38'"proximate the sleeve 44'" is contained. After the overcoat layer 42'" isformed upon the intermediate tube 3'", an outer bactericide releaselayer 61'" is formed and a pair of fluid conduit openings 56 arepreferably created, most preferably punched, to permit fluid to passinto or out of the lumen 8'" proximate the distal end 16'". It will beappreciated that, although the overcoat layer 42'" and the wall 11'" ofthe tube 2'" are shown in FIG. 49 to be separate elements, when made ofidentical polymeric materials, as is the case with the most preferredembodiments of the present invention which are made of silicone rubber,the wall 11'" and the overcoat layer 42'" will be bonded together wherethey interface with one another so that it is virtually impossible todistinguish between the two and so that there is preferably no part linein spite of the fact that a part line is shown in FIGS. 47 and 49. Inthe preferred embodiments, where these elements are enjoined together,it will be appreciated that they form an integral membrane or wall.

The specific procedures used to form the present elongated catheter 4'"will include steps similar to the steps used for similar purposes asdescribed hereinabove.

In the Applicants' use of the preferred methods of the presentinvention, balloon and sleeve fabrication is almost completelyautomated. Entire sets of sleeved balloon catheters 5' are manufacturedsimultaneously. The preferred pallet 24 has 400 spring steel supportrods 26 attached to a pallet in 20 rows of 20 rods, wherein each of therods 26 is about 1 inch from each adjacent rod. Single and double lumentubing (not shown) is preferably made by extrusion processes known tothose of skill in the art. The tubes 2 and 2' are cut to length as thetubing leaves the extruder (not shown). An opening 12' is created in theouter surface 14' of the double lumen tubes 2', preferably with a hollowdrill bit or drill tube (not shown), so as to communicate with thecapillary lumen 6' in those tubes 2'. The distal portion 6a' of thecapillary lumen 6', located between the distal end 16' of the tube 2'and the capillary lumen access opening 12', is then injected with ameasured amount of a polymeric bonding composition, preferably siliconerubber, so that the distal portion 6a' is filled and sealed. A roundedtip 20' is then formed at the distal end 16, of the double lumen tube2', preferably by inserting the tube 2' in a molding device (not shown).

Referring now also to FIG. 39, another preferred embodiment of thepresent invention is illustrated in this embodiment of the presentinvention as sleeved Foley catheter 4". It is very similar to thecatheter shown in FIG. 38 except that the space between the ballooncavity 54" and the sleeve cavity 45", has been decreased so that it willaccommodate the urethral sphincter of the bladder. In addition, thevolume of the lubricating substance 38"" in the sleeve cavity 45" issignificantly more than that shown in FIG. 38. This is accomplished byincreasing the thickness of the lubricating substance 38 which is coatedonto the intermediate tube carrying the manufacturing process. Theincrease in the thickness of the lubricating substance 38" allows thesleeved Foley catheter 4" to provide a very soft, "cushy", conformingexterior surface 9" proximate the sleeve 44" which can accommodatevariations in the surfaces with which the catheter 4" comes intocontact.

Referring now also to FIG. 40, the sleeved Foley catheter 4" shown inFIG. 39 is shown when inserted into a urethral tract 74 of a woman 70the balloon portion 58" of the catheter 4" resides within the bladder 72of the woman 70. The balloon portion 58" is expanded to retain thecatheter 4" in the urethral tract 74. The harsh volume of lubricatingsubstance 38" in the sleeve cavity 45" is shown to provide a exteriorsurface 9" proximate the sleeve 44" which conforms to the wall of theurethral tract 74. The lubricating substance 38" also allows the innerwall 46" or conduit portion 46" of the catheter 4" to move back andforth within the urethral tract 74" to a limited degree withoutdisrupting the interface between the exterior surface 9" proximate thesleeve 44" and the adjacent body tissues of the urethral tract. Thisallows the catheter 4" to move in all directions to a limited degreewithout disrupting this interface, thereby increasing the comfort of thepatient in which the catheter 4" resides.

In the most preferred embodiments of the present method, 400 of theintermediate tubes 3' are then mounted vertically on rigid spring steelsupport rods 26' on a pallet 24' in the manner previously described. Thepallet 24' is then moved via a transporting mechanism 22 (see FIG. 28)over a series of dip tanks as follows in the following example whichwill further disclose preferred elements of the present invention.

Example I

(A) The pallet 24' is stopped over a first tank 33', which containswhite USP petrolatum heated to about 60° C. (about 140° F.). The tank israised so as to immerse the intermediate tubes 3' into the petrolatum tosuch a depth that the petrolatum reaches the proximal end of the desiredsleeve location. The dip tank 33' is then lowered and a portion of theouter surface 14' of the intermediate tubes 3' are coated withpetrolatum. This portion extends from the general point at which theproximal end of the resilient sleeve 44' will begin, to the distal end20a' of the tip 20' of the intermediate tube 3'. This step is repeatedwhen it is desireable to build up the thickness of the lubricatingsubstance and the resulting volume of the sleeve cavity so as toincrease the resulting increase in the outside diameter of theparticular catheter over the circumferential diameter of the conduitportion or tube 2 or 2' of this present invention.

(B) The pallet 24' is then automatically advanced and stopped over asecond dip tank 35' which contains white USP petrolatum heated to about120° C. (about 250° F.). The second dip tank 35' is raised so as toimmerse the intermediate tubes 3' into the super-heated petrolatum sothat the super-heated petrolatum comes into contact with the petrolatumcoating 38' on outer surface 14' of the intermediate tube 3' from theprior dipping step up to a general location where a distal end of theresilient sleeve 44' will end. The second dip tank 35' is then lowered.This dipping step causes the coating of petrolatum from the priordipping step to be largely removed from the portions 14a' the outersurface 14' below a location where the distal end of the resilientsleeve 44' will be generally located (designated by dashed line B) tothe distal end 20a' of the tip 20' of the intermediate tube 3'. Someresidual petrolatum may remain on the outer surface 14' of theintermediate tube 3' in this area of the outer surface 14'. However,most of the petrolatum is removed.

(C) The pallet 24' is then automatically advanced and stopped over athird dip tank 37' containing mineral spirits heated to about 200° F.The third dip tank 37' is then raised so as to immerse the intermediatetubes 3' into the mineral spirits to the same depth as they wereimmersed in the super-heated petrolatum in the second dip tank 35'. Thetank 37' is then lowered and all but a trace amount of the petrolatum isremoved from the outer surface 14' located generally below the dashedline B, which will eventually be proximate the sleeve 44'.

(D) The pallet 24' is then automatically advanced and stopped over afourth dip tank 40' containing a volatile organic solvent such astoluene, trichloromethane or the like. The fourth tank 40' is thenraised to immerse the intermediate catheters 3 to the same depth aspreviously immersed in the second and third tanks 35' and 37', therebyremoving essentially all traces of the petrolatum from this portion ofthe outer surface 14'. The intermediate catheter tube 3' now has a band38' of semi-solid petrolatum located around the axial circumference ofthe intermediate tube 3' in the location where the sleeve cavity 45'will be created.

(E) The pallet 24' is then stopped over a fifth, sixth, seventh andeighth dip tank, 41', 43', 51' and 53', respectively, where the stepsenumerated in steps A, B, C, and D, respectively, are repeated with thefollowing variation. When the pallet 24' is stopped over the fifth diptank 41', the intermediate tubes 3' are immersed only up to a locationproximate the dashed line designated C as shown in FIGS. 18 and 19. Whenthe pallet 24' is subsequently stopped in series over dip tanks 43',47'and 49', the intermediate tubes 3' on the pallet 24' are onlyimmersed up to a location proximate the dashed line D as shown in FIGS.32 and 33. Following these steps, the petrolatum is stripped from theportion 14a' of the outer surface 14' located below the locationproximate the dashed line designated line D. The petrolatum not onlycoats the portion 14c' of the outer surface 14' located in this area,but also fills a portion of the capillary lumen 6' and plugs thecapillary lumen access opening 12', which will eventually be used toinflate the balloon portion 58' of the completed Foley catheter 4'.

(F) After the last of these dip tanks (53') is lowered, the pallet 24'is automatically advanced to a ninth dip tank 55' containing alow-solids silicone rubber/solvent dispersion which is effective tominimize any disruption of the integrity of the petrolatum coatings 38'or 40' remaining on the intermediate tube 3' proximate the portions 14e'and 14c' of the outer surface 14' where the sleeve cavity 45' ballooncavity 54' will be created during subsequent dipping steps. The ninthtank 51' is then raised to immerse the intermediate tube 3' in thesolution up to a location above the dashed line designated in A in FIG.33. This step can be subsequently repeated at intervals, preferablyallowing time for significant solvent evaporation, either in the sametank or in a subsequent tank containing a greater concentration ofsilicone rubber, until the overcoat layer 42' and the balloon portion58' of the overcoat layer 42' have a desired balloon thickness. The diptank 55' is then lowered, and the overcoat layer 42' is allowed to airdry for about 15 minutes. The pallet 24' is advanced to a tenth dip tank57 containing a silicone rubber/nitrofuran compound fluid mixture ordispersion 17', and the tubes 3' are completely immersed again. Thepreferred thickness of the resilient sleeve 44' and the balloon portion58' is 17.5 thousandths of an inch (plus or minus 2.5 thousandths of aninch), although a modest increase is not considered to be detrimental tothe function thereof. Where subsequent silicone rubber dip tanks areprovided, the concentration of silicone rubber in the subsequent tanksare preferably greater than the concentration of the silicone rubber inthe ninth tank 51. It is also desirable to alter the silicone rubberused in a final coating to provide greater sheen and a smoother finish,however, the concentration and the solvent may be adjusted as deemedappropriate.

(G) The pallet 24' is then advanced through a drying area where solventsare allowed to evaporate, and then through a two port (liquid/hot air)heat cure step, where the sleeved balloon catheters 5' formed by thisprocess are cured, first in a hot liquid bath at 160° F. for 15 minutes,and then in hot air (200° F.), or at a temperature just below theboiling point of any solvent used in any of the silicone rubber dipdispersions, for an hour. For toluene this temperature is about 200° F.

(H) After the heat cure, the sleeved balloon catheters 5' are allowed tocool and are then removed from the support rods 26'. The proximal ends30' of each of the balloon catheters 4 is then inserted into aninjection molding apparatus (not shown), which forms the end piece 46'of the completed sleeved Foley catheter 4'.

(I) The completed Foley catheters 5 are then finished by punching afluid conduit access opening 56' in the exterior surface 61' such thatit communicates with the fluid conduit lumen 8' in a location below ordistal to the balloon portion 58' of the overcoat layer 42'.

(J) The completed Foley catheters 4' are then sent through the testsequence described hereinabove, during which the balloon portion 58' ofeach completed Foley catheter 4' is inflated and the petrolatum band 40'within the balloon cavity 54' is largely removed.

Referring now also to FIGS. 42a, 42b and 42c, the present inventionprovides a method of making sleeved Foley catheters 4' including thefollowing steps:

(A) Providing a tube having an outer surface and first and secondlumens;

(B) Cutting the tube to a desired length;

(C) Creating a first lumen access opening in the outer surface tocommunicate with the first lumen;

(D) Filling the first lumen with a polymeric bonding composition up tothe first lumen access opening from an end nearest the first lumenaccess opening;

(E) Sealing the end of the tube nearest the first lumen access opening;and

(F) Securing the tube to a movable pallet.

These steps are followed by the following steps:

(A) Coating a first portion of the outer surface and plugging the firstlumen access opening with a removable bond preventing lubricating agent;

(B) Stripping the coating of removable bond preventing lubricating agentaway from a second portion of the outer surface adjacent to the firstportion;

(C) Simultaneously coating a third portion of the outer surface adjacentto the second portion thereof and plugging the first lumen accessopening with a removable bond preventing agent;

(D) Stripping the coating of removable bond preventing agent away from afourth portion of the outer surface adjacent to and below the thirdportion thereof;

(E) Coating the outer surface and the remaining coating of removablebond preventing agent with an overcoat layer of a suitable film formingpolymeric bonding composition;

(F) Coating the overcoat layer with a silicone rubber/bactericidecoating mixture to form an outer bactericide release layer;

(G) Air drying outer bactericide release layer; and

(H) Curing the overcoat layer.

Following those steps, methods of the present invention include thefollowing steps:

(A) Securing an end piece to the end of the tube furthest from the firstlumen access opening;

(B) Simultaneously testing the balloon portion of the resulting catheterand substantially removing the removable preventing bond agent from thefirst portion of the outer surface and the first lumen access opening;

(C) Further testing the catheter capillary lumen and the balloon portionfor leaks;

(D) Punching a second lumen access opening in an exterior surface of thecatheter to communicate with the second lumen;

(E) Packaging the resulting sleeved Foley catheters; and

(F) Sterilizing the sleeved Foley catheters.

In another preferred embodiment of the present invention, following thesecuring of a plurality of intermediate tubes 3' to the transportablepallet 24', balloon catheters are produced as follows:

(A) The pallet 24' is stopped over a first tank 33', which containswhite USP petrolatum heated to about 60° C. That tank 33' is then raisedso as to immerse the intermediate tubes 3' into the petrolatum to such adepth that the petrolatum reaches the proximal end of the desiredresilient sleeve location proximate the dashed line designated A in FIG.29. The dip tank 33' is then lowered and a portion of the outer surface14' of the intermediate tubes 3' are coated with petrolatum. Thisportion extends from the general point at which the proximal end of theresilient sleeve 44' will begin, to the distal end 2a' of the tip 20' ofeach intermediate tube 3'. In other embodiments, this step can berepeated to increase the thickness of the lubricant coating 38', as wellas the ultimate volume of the sleeve cavity 45' and the size of theoutside diameter of the catheter 5' proximate the sleeve 44'.

(B) The steps outlined in paragraphs B, C and D of Example I presentedhereinabove, are then followed generally as outlined in Example I.

(C) The pallet 24' is then stopped over a fifth dip tank 41', whichcontains a liquid soap (Liquid Ivory Soap from Proctor & Gamble Co.,Cincinnati, Ohio 45202). The soap is held at room temperature (betweenabout 60°-80° F., preferably 65°-72° F.). The fifth dip tank 41' israised so as to immerse the intermediate tubes 3' into the liquid soapso that the soap coats the tubes 3' up to the dashed line designated bythe letter C in FIG. 32. The dip tank 41' is then lowered and the liquidsoap forms a semi-solid coating 40' on the outer surface 14' of each ofthe intermediate tubes 3' extending from line designated C to the distalend 20a' of the tip 20' of each of the intermediate tubes 3'.

(D) The pallet 24 is then automatically advanced and stopped over asixth dip tank 43' which contains an aqueous solution containing a traceof a suitable wetting agent or surfactant. In a preferred embodiment,three gallons of water is mixed with two ounces of a suitablesurfactant. The surfactant will generally be less than one percent ofthe total volume of the solution. A sixth dip tank 43' is then raised soas to immerse the intermediate tubes 3' in the aqueous fluid up to thedashed line designated by the letter D in FIGS. 32 and 33. The sixth diptank 43' is then lowered and the semi-solid liquid soap coating theportion 14a' of the outer surface 14' below the dashed line designated Dis substantially removed.

(E) The pallet 24' is then automatically advanced and stopped over aseventh dip tank 51' containing water. The seventh dip tank 51' is thenraised and the intermediate tubes 3' are immersed in the water up to theline designated D as in the prior dipping step. The seventh dip tank 51'is then lowered and virtually all of the liquid soap is removed from theportion 14a' of the outer surface 14' below the line designated D.

(F) The pallet 24' is then automatically advanced and stopped over aeighth dip tank 53' containing a low-solids silicone rubber/solventdispersion which is effective to minimize any disruption of theintegrity of the liquid soap coating 40' remaining on each of theintermediate tubes proximate the portion 14c' of the outer surface 14'where the balloon cavity 54 will be created during subsequent dippingsteps (the portion between the dashed lines designated C and D). Theeighth tank 53' is then raised to immerse intermediate tubes 3' in thesilicone rubber dispersion. It will be appreciated that any suitablesolvent for providing a suitable dispersion of silicone rubber andcoating the particular lubricating agent may be used. It is alsobelieved to be possible to use aqueous solvents, however, they are notpreferred at present. It will also be appreciated that this step can berepeated at subsequent intervals, preferably long enough to permitsignificant solvent evaporation, to add to the thickness of the overcoatlayer 42' and the balloon portion 58' of the overcoat layer 42'.However, further steps, involving different solutions can also follow.

(G) The fourth dip tank 39' is then lowered and the silicone rubber,coating portions of the outer surface 14' as well as the coating ofpetrolatum 38' and the coating of soap 40', is allowed to dry. Thepallet 24' is then advanced again to a ninth dip tank 55' containing adifferent silicone rubber dispersions having a solids content which ishigher than the solids content in the eighth dip tank 53'. Theintermediate tubes 31' are immersed again in the subsequent siliconerubber dispersion when the ninth dip tank 55' is raised. The ninth diptank 55' is then lowered, and the silicone rubber, coating the tubes 3',is allowed to dry.

(H) The pallet 24' is then automatically advanced again to a tenth diptank 53 containing a silicone rubber/nitrofuran compound fluid mixture17' including a silicone rubber and silicone fluid in trichloroethane,mixed with a nitrofuran compound, preferably nitrofurazone particleshaving a mean particle diameter of 100 microns or less. The tubes 3' aredipped again as before and the tenth dip tank 51' is then lowered andthe silicone rubber coating the tubes 3' is allowed to dry.

(G) The pallet 24' is then advanced through a drying step followed by atwo-part (liquid/hot air) heat cure step, and each completed sleevedballoon catheter 5' is then secured to an end piece 46', tested,provided with a fluid conduit access opening 56', packaged andsterilized.

The automated system that Applicants claim will permit completed sleevedFoley catheters 4' to be manufactured at the rate of about 1,600catheters per hour. Because virtually no handwork is involved in theballoon and sleeve construction, the catheters 4' produced will beconsistent and of very high quality. The exterior surface 62' issmoother than hand-glued balloons, and the outside diameter of theballoon portion 58' is essentially identical to the outside diameter ofother portions of the completed Foley catheters 4'. It will beappreciated that larger outside diameter balloon portions areundesirable since they are somewhat more difficult to insert andwithdraw, and cause additional trauma upon withdrawal. In addition, byeliminating the hand labor involved in adhering the balloon portion 58'to the intermediate tube 3' in the manufacture of silicone rubberballoon catheters 5', by specifically eliminating the separate step offabricating the balloon portion, which also requires hand labor, and byeliminating the significant impact on yield resulting from handprocessing errors, the applicants, new process will permit directproduction cost for silicone rubber balloon catheters of all types to bereduced by about 25-50% over the cost estimated for the prior artsilicone rubber balloon catheters.

It is to be understood, however, that even though numerouscharacteristics and advantages of the present invention have been setforth in the foregoing description, together with details of thestructure and function of the invention, the sequence or order of thespecific steps, or the actual compositions, solvents, temperatures,environmental conditions and the like employed for each step, it will beappreciated the disclosure is illustrative only, and that changes may bemade in detail, especially in matters of shape, size, arrangement ofparts or sequence or elements of events within the principles of theinvention to the full extent indicated by the broad general meaning ofthe terms in which the appended claims are expressed.

What is claimed is:
 1. A sustained release bactericidal cannula, throughwhich aqueous biological fluids can pass for residence within a portionof a human body said bactericidal cannula comprising: a tube having aninner surface, defining an internal lumen, and an outer surface, saidtube having a polymeric matrix and an antibacterial agent residingwithin at least a portion of the polymeric matrix; wherein the polymericmatrix includes cured silicone rubber, said antibacterial agent is afinely divided nitrofuran compound which is soluble in water andeffective to prevent proliferation of certain bacteria in an otherwise,growth supporting, aqueous environment when dissolved in the aqueousenvironment to the limit of its solubility therein at 37° C., thesolubility of the nitrofuran compound is about 0.2% by weight or less inwater at a pH of about 6 and a temperature of about 25° C., and theantibacterial agent can diffuse out of the polymeric matrix and into anaqueous biological environment when the polymeric matrix comes intocontact with the aqueous biological environment; and wherein at least afinite portion of the polymeric matrix proximate the outer surfaceincludes an amount of from about 10 to about 60% by weight of thenitrofuran compound, and the amount of the nitrofuran compound in thefinite portion of the polymeric matrix, and the solubility of thenitrofuran compound, cooperate to provide a potential for a sustainedrelease diffusion of the antibacterial agent into the aqueous biologicalfluids within the human body, during normal therapeutic use of thecannula within the human body, so long as the aqueous biological fluidsare not saturated with the antibacterial agent, such that theantibacterial agent within the finite portion of the polymeric matrixcan continue to diffuse into the aqueous biological fluids within thehuman body in an amount effective to prevent proliferation of certainbacteria immediately adjacent to the cannula in aqueous biologicalenvironments for a period of not less than about three weeks.
 2. Thesustained release bactericidal cannula of claim 1 wherein theantibacterial agent has a solubility in water at a pH of about 6 and atemperature of about 25° C. of from about 0.001 to about 0.2% by weight.3. The sustained release bactericidal cannula of claim 2 wherein theantibacterial agent is selected from the group consisting ofnitrofurazone, nitrofurantoin, furaltadone, furazolidone, nifuradene,nidroxyzone, nifuroxime and nihydrazone.
 4. The sustained releasebactericidal cannula of claim 2 wherein the antibacterial agent isselected from the group consisting of nitrofurazone, nitrofurantoin,furaltadone and furazolidone.
 5. The sustained release bactericidalcannula of claim 2 wherein the antibacterial agent is nitrofurazone. 6.The sustained release bactericidal cannula of claim 1 wherein thepolymeric matrix includes silicone fluid.
 7. The sustained releasebactericidal cannula of claim 1 wherein the finite portion of thepolymeric matrix contains an amount of a water soluble anti-inflammatoryagent sufficient to diffuse into the aqueous biological fluids andreduce inflammation within the human body immediately adjacent to thecannula.
 8. A sustained release bactericidal urinary catheter forresidence within a urinary tract of a human body, said bactericidalurinary catheter comprising: a tube having an inner surface, defining aninternal lumen, and an outer surface, said tube having a polymericmatrix and an antibacterial agent residing within the polymeric matrix,wherein the polymeric matrix includes silicone rubber, the antibacterialagent is a nitrofuran compound which is soluble in water and effectiveto reduce proliferation of bacteria in an otherwise growth supporting,aqueous environment when dissolved in the aqueous environment to thelimit of its solubility therein at 37° C., and the antibacterial agentcan diffuse out of the polymeric matrix and into an aqueous biologicalenvironment when the polymeric matrix comes into contact with theaqueous biological environment; and wherein the antibacterial agent hasa solubility in water, at a pH of about 6 and a temperature of about 25°C., of about 0.2% by weight or less, and at least a finite portion ofthe polymeric matrix proximate the outer surface contains an amount offrom about 10 to about 60% by weight of the nitrofuran compound, and theamount of the nitrofuran compound in the finite portion of the polymericmatrix and the solubility of the nitrofuran compound cooperate toprovide a potential for a sustained release diffusion of theantibacterial agent into the aqueous biological fluids within the humanbody during normal therapeutic use of the catheter within the urinarytract so long as the aqueous biological fluids are not saturated withthe antibacterial agent, such that the antibacterial agent within thefinite portion of the polymeric matrix can continue to diffuse into theaqueous biological fluids within the urinary tract in an amounteffective to prevent proliferation of certain bacteria immediatelyadjacent to the catheter in aqueous biological environments for a periodof not less than about three weeks.
 9. The sustained releasebactericidal urinary catheter of claim 8 wherein at least a portion ofthe polymeric matrix includes a cured silicone rubber matrix, and thecured silicone matrix includes silicone fluid.
 10. The sustained releasebactericidal urinary catheter of claim 8 wherein the nitrofuran compoundis a finely divided solid compound residing within the polymeric matrixand the outer surface is a smooth polymeric surface through which thenitrofuran compound can diffuse when the outer surface comes intocontact with an aqueous environment.
 11. The sustained releasebactericidal urinary catheter of claim 10 wherein the antibacterialagent is selected from the group nitrofurazone, nitrofurantoin,furaltadone and furazolidone.
 12. The sustained release bactericidalurinary catheter of claim 8 wherein the antibacterial agent has asolubility in water at a pH of about 6 and a temperature of about 25° C.of about 0.001 to about 0.2% by weight.
 13. The sustained releasebactericidal urinary catheter of claim 11 wherein the antibacterialagent is nitrofurazone.
 14. The sustained release bactericidal urinarycatheter of claim 8 wherein the finite portion of the polymeric matrixcontains an amount of a water soluble anti-inflammatory agent sufficientto diffuse into the aqueous biological fluids and reduce inflammationwithin the human body immediately adjacent to the catheter.
 15. Thesustained release bactericidal urinary catheter of claim 14 wherein thewater soluble anti-inflammatory agent is a hydrocortisone compound. 16.The sustained release bactericidal urinary catheter of claim 15 whereinthe hydrocortisone compound has a solubility in water of less than about0.1% by weight.
 17. The elongated sustained release bactericidal cannulaof claim 16 wherein the nitrofuran compound is a solid powder having amean particle diameter of not more than about 200 microns.
 18. Theelongated sustained release bactericidal cannula of claim 16 furthercomprising an expandable balloon having an expandable balloon cavity, asecond lumen in communication with the expandable balloon cavity, and anenclosed sleeve cavity wherein the enclosed sleeve cavity is locatedbetween the respective interior and exterior surfaces and encircling thefirst lumen in a position removed from the expandable balloon cavity,wherein a first portion of the silicone rubber coating coats theexterior surface proximate the expandable balloon, said first portionstretching when the expandable balloon expands, wherein the rate ofdiffusion of the nitrofuran compound can increase when the first portionstretches.
 19. A sustained release bactericidal urinary catheter forresidence within a urinary tract of a human body, the sustained releasebactericidal urinary catheter comprising: an interior surface defining afirst lumen, an expandable balloon having an expandable balloon cavity,a second lumen in communication with the expandable balloon cavity, andan exterior surface, wherein the exterior surface is coated to form acoating having a silicone rubber polymeric matrix containing anantibacterial agent capable of diffusing out of the polymeric matrix inaqueous environments, the antibacterial agent is a finely dividednitrofuran compound which is soluble in water, the solubility of thenitrofuran compound is about 0.2% by weight or less in water at a pH ofabout 6 and a temperature of about 25° C., and the amount of thenitrofuran compound in the silicone rubber polymeric matrix is an amountin a range from about 10 to about 60% by weight of the coating, andwherein the amount of the nitrofuran compound in the coating and thesolubility of the nitrofuran compound cooperate to provide a potentialfor a sustained release diffusion of the antibacterial agent into theaqueous biological fluids within the human body during normaltherapeutic use of the catheter within the urinary tract, so long as theaqueous biological fluids are not saturated with the antibacterialagent, such that the antibacterial agent within the coating can continueto diffuse into the aqueous biological fluids within the urinary tractin an amount effective to prevent proliferation of certain bacteriaimmediately adjacent to the catheter in aqueous biological environmentsfor a period of not less than about three weeks.
 20. The sustainedrelease bactericidal urinary catheter of claim 19 wherein the siliconerubber polymeric matrix is a cured silicone rubber matrix, the siliconerubber polymeric matrix includes silicone fluid, and the nitrofurancompound is selected from the group consisting of nitrofurazone,nitrofurantoin, furaltadone, furazolidone, nifuradene, nidroxyzone,nifuroxime and nihydrazone.
 21. The sustained release bactericidalurinary catheter of claim 19 wherein the coating contains an amount of awater soluble anti-inflammatory agent sufficient to diffuse into theaqueous biological fluids and reduce inflammation within the human bodyimmediately adjacent to the catheter.
 22. The sustained releasebactericidal urinary catheter of claim 21 wherein the coating containsan amount of the antibacterial agent in a range from about 10 to about60% by weight thereof and the antibacterial agent is a nitrofurancompound having a solubility of about 0.2% by weight or less in water ata pH of about 6 and a temperature of about 25° C.
 23. An elongatedsustained release bactericidal cannula comprising an interior surface,defining a first lumen, an exterior surface and an enclosed sleevecavity located between the respective interior and exterior surfaces andencircling the first lumen, said elongated bactericidal cannula furthercomprising a resilient sleeve portion encircling the first lumen andsaid sleeve cavity, said sleeve cavity containing a lubricatingsubstance, wherein the bactericidal cannula further includes a siliconerubber coating containing an amount of an antibacterial agent effectiveto diffuse out of the silicone rubber coating when immersed in anaqueous environment, the silicone rubber is a cured silicone rubbermatrix containing silicone fluid, the antibacterial agent is a finelydivided nitrofuran compound which is soluble in water and hasantibacterial activity in aqueous biological environments when dissolvedin such an aqueous biological environment to the limit of its solubilityin water at 37° C., the solubility of the nitrofuran compound is about0.001 to 0.2% by weight in water at a pH of about 6 and a temperature ofabout 25° C., and the amount of the nitrofuran compound in the siliconerubber coating is an amount in a range of from about 10 to about 60% byweight of the coating.
 24. The elongated sustained release bactericidalcannula of claim 23 wherein the antibacterial agent is selected of thegroup consisting of nitrofurazone, nitrofurantoin, furaltadone andfurazolidone.
 25. A method of catheterizing a patient, the patienthaving a urinary tract through which aqueous fluids can pass, saidmethod comprising the steps of:(a) providing a sustained releasebactericidal urinary catheter including an interior surface defining afirst lumen and an exterior surface, wherein the exterior surface iscoated with a cured silicone rubber polymeric matrix forming a coatingcontaining an antibacterial agent capable of diffusing out of the curedsilicone rubber polymeric matrix in aqueous environments, wherein theantibacterial agent is a nitrofuran compound which soluble having asolubility of about 0.2% by weight or less in water at a pH of about 6and a temperature of about 25° C., and the amount of the nitrofurancompound in the cured polymeric matrix is in a range of from about10-60% by weight of the total weight of the cured silicone rubberpolymeric matrix, and wherein the amount of the nitrofuran compound inthe coating and the solubility of the nitrofuran compound cooperate toprovide a potential for a sustained release diffusion of theantibacterial agent into the aqueous biological fluids within the humanbody during normal therapeutic use of the catheter within the urinarytract so long as the aqueous biological fluids are not saturated withthe antibacterial agent, such that the antibacterial agent within thecoating can continue to diffuse into the aqueous biological fluidswithin the urinary tract in an amount effective to prevent proliferationof certain bacteria immediately adjacent to the catheter in aqueousbiological environments for a period of not less than about three weeks;(b) placing the catheter within the urinary tract for residence therein,wherein the aqueous fluids within the urinary tract interact with thecured silicone polymeric matrix, and a sufficient amount of theantibacterial agent is provided such that the antibacterial agent candiffuse into the aqueous fluids for a period of at least about threeweeks such that the aqueous fluids are less capable of sustainingbacterial growth therein during this period as a result of the presenceof the antibacterial agent.
 26. The method of claim 25 wherein thenitrofuran is selected from the group consisting of nitrofurazone,nitrofurantoin, furaltadone, furazolidone, nifuradene, nidroxyzone,nifuroxime and nihydrazone.
 27. The method of claim 25 wherein the stepof placing includes retaining the catheter within the urinary tract fora period of at least about 20 days, wherein the antibacterial agentwithin the polymeric matrix continues to diffuse into the aqueous fluidin the urinary tract as the aqueous fluid passes therethrough.
 28. Asustained release bactericidal cannula through which aqueous biologicalfluids can pass, said bactericidal cannula comprising:a tube having asurface, the surface being coated at least in part by a polymericmaterial, the polymeric material providing a polymeric matrix, thepolymeric matrix containing an antibacterial agent which is at leastpartially soluble in water, wherein the antibacterial agent can diffuseout of the polymeric matrix and into an aqueous biological environmentwhen the polymeric matrix comes into contact with such an aqueousbiological environment, wherein said antibacterial agent is a nitrofurancompound which is at least partially soluble in water and effective toprevent proliferation of certain bacteria in an otherwise, growthsupporting, aqueous environment when dissolved in the aqueousenvironment to the limit of its solubility therein at 37° C.
 29. Thesustained release bactericidal cannula of claim 28 wherein the polymericmatrix includes cured silicone rubber.
 30. The sustained releasebactericidal cannula of claim 29 wherein the polymeric matrix includessilicone fluid.
 31. The sustained release bactericidal cannula of claim28 wherein the antibacterial agent has a solubility in water at a pH ofabout 6 and a temperature of about 25° C. of from about 0.001 to about0.2% by weight.
 32. The sustained release bactericidal cannula of claim28 wherein the antibacterial agent is a finely divided nitrofurancompound which is soluble in water.
 33. The sustained releasebactericidal cannula of claim 32 wherein the antibacterial agent isselected from the group consisting of nitrofurazone, nitrofurantoin,furaltadone, furazolidone, nifuradene, nidroxyzone, nifuroxime andnihydrazone.
 34. The sustained release bactericidal cannula of claim 32wherein the antibacterial agent is selected from the group consisting ofnitrofurazone, nitrofurantoin, furaltadone and furazolidone.
 35. Thesustained release bactericidal cannula of claim 32 wherein theantibacterial agent is nitrofurazone.
 36. The sustained releasebactericidal cannula of claim 32 wherein the nitrofuran compound is asolid powder having a mean particle diameter of not more than about 200microns.
 37. The sustained release bactericidal cannula of claim 28wherein a finite portion of the polymeric matrix contains an amount of awater soluble anti-inflammatory agent sufficient to diffuse into theaqueous biological fluids and reduce inflammation within a portion ofthe human body immediately adjacent to the cannula.
 38. The sustainedrelease bactericidal cannula of claim 37 wherein the water solubleanti-inflammatory agent is a hydrocortisone compound.
 39. The sustainedrelease bactericidal cannula of claim 38 wherein the hydrocortisonecompound has a solubility in water of less than about 0.1% by weight.40. The sustained release bactericidal cannula of claim 28, said tubehaving an outer surface and inner surface, the inner surface defining aninternal lumen, the outer surface being coated at least in part by thepolymeric material, wherein the polymeric matrix provided by thepolymeric material on the outer surface contains an amount of theantibacterial agent sufficient to diffuse out of the polymeric matrixwherein the polymeric matrix comes into contact with the aqueousbiological environment.
 41. The sustained release bactericidal cannulaof claim 40 wherein the internal lumen is a first lumen, said cannulafurther including an expandable balloon having an expandable ballooncavity, a second lumen in communication with the expandable ballooncavity.
 42. The sustained release bactericidal cannula of claim 40wherein the cannula further includes a sleeve cavity encircling theinternal lumen within the cannula, said sleeve cavity being locatedbetween the outer surface and the inner surface.
 43. The sustainedrelease bactericidal cannula of claim 42 further including an expandableballoon, an expandable balloon cavity, and a second lumen incommunication with the expandable balloon cavity.
 44. A sustainedrelease bactericidal cannula through which aqueous biological fluids canpass, said bactericidal cannula being made from a tube having an uncuredsilicone rubber outer surface, said bactericidal cannula being made by aprocess comprising the steps of:(a) providing an antibacterial agentcontaining mixture including uncured silicone rubber and finely dividedparticles of a solid antibacterial agent, wherein the antibacterialagent is a nitrofuran compound having a solubility in water of 0.2% byweight or less; (b) coating at least a portion of the outer surface ofthe tube with the antibacterial agent containing mixture to form anuncured nitrofuran containing silicone rubber outer layer; and (c)curing the silicone rubber of both the uncured silicone rubber outersurface and the uncured nitrofuran containing silicone rubber outerlayer to form a cured antibacterial agent containing silicone rubberouter layer bonded to the silicone rubber outer surface; wherein thestep of providing includes providing an antibacterial agent containingmixture containing a sufficient amount of the nitrofuran compound thatthe cured antibacterial agent containing silicone rubber outer layercontains about 10 to about 60 percent by weight of the nitrofurancompound; wherein the outer surface of the resulting bactericidalcannula is coated at least in part by a polymeric material includingsilicone rubber, the polymeric material providing a polymeric matrix,the polymeric matrix containing the antibacterial agent, wherein theantibacterial agent can diffuse out of the polymeric matrix and into anaqueous biological environment when the polymeric matrix comes intocontact with such an aqueous biological environment, wherein saidantibacterial agent is a nitrofuran compound which is at least partiallysoluble in water and effective to prevent proliferation of certainbacteria in an otherwise, growth supporting, aqueous environment whendissolved in the aqueous environment to the limit of its solubilitytherein at 37° C.
 45. The sustained release bactericidal cannula ofclaim 44 wherein the antibacterial agent is selected from the groupconsisting of nitrofurazone, nitrofurantoin, furaltadone, furazolidone,nifuradene, nidroxyzone, nifuroxime and nihydrazone.
 46. The sustainedrelease bactericidal cannula of claim 45 wherein the finite portion ofthe polymeric matrix contains an amount of a water solubleanti-inflammatory agent sufficient to diffuse into the aqueousbiological fluids and reduce inflammation within a portion of the humanbody immediately adjacent to the cannula.
 47. The sustained releasebactericidal cannula of claim 46 wherein the water solubleanti-inflammatory agent is a hydrocortisone compound.